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WARNING: MALIGNANCIES AND SERIOUS INFECTIONS Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 ) WARNING: MALIGNANCIES AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 )
1 INDICATIONS AND USAGE PROGRAF is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants. ( 1.1 ) 1.1 Prophylaxis of Organ Rejection in Kidney, Liver, Heart, or Lung Transplant PROGRAF ® is indicated for the prophylaxis of organ rejection, in adult and pediatric patients receiving allogeneic kidney transplant [see Clinical Studies ( 14.1 )], liver transplant [see Clinical Studies ( 14.2 )], heart transplant [see Clinical Studies ( 14.3 )], or lung transplant [see Clinical Studies ( 14.4 )] in combination with other immunosuppressants.
2 DOSAGE AND ADMINISTRATION • Intravenous (IV) use recommended for patients who cannot tolerate oral formulations (capsules or suspension). ( 2.1 , 2.2 ) • Administer capsules or suspension 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 dosage adjustments for African-American patients ( 2.2 ), hepatic and renal impaired. ( 2.4 , 2.5 ) • For complete dosing information, see 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 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL With MMF/IL-2 receptor antagonist 0.1 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 4-11 ng/mL Liver Transplant With corticosteroids only 0.1-0.15 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant With azathioprine or MMF 0.075 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL Lung Transplant With azathioprine or MMF 0.075 mg/kg/day Patients with cystic fibrosis may require higher doses due to lower bioavailability. capsules, divided in two doses, every 12 hours Month 1-3: 10-15 ng/mL Month 4-12: 8-12 ng/mL PEDIATRIC Patient Population Initial Oral Dosage (formulation) Whole Blood Trough Concentration Range Kidney Transplant 0.3 mg/kg/day capsules or oral suspension, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Liver Transplant 0.15-0.2 mg/kg/day capsules or 0.2 mg/kg/day oral suspension, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant 0.3 mg/kg/day Dose at 0.1 mg/kg/day if antibody induction treatment is administered. capsules or oral suspension, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Lung Transplant 0.3 mg/kg/day , capsules or oral suspension, divided in two doses, every 12 hours Weeks 1-2: 10-20 ng/mL Week 2 to Month 12: 10-15 ng/mL MMF= Mycophenolate mofetil 2.1 Important Administration Instructions PROGRAF should not be used without supervision by a physician with experience in immunosuppressive therapy. PROGRAF capsules and PROGRAF Granules 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 PROGRAF 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 PROGRAF injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter.
risk of anaphylactic reactions that occurred with injectables containing castor oil derivatives [see Warnings and Precautions ( 5.9 )] . Patients receiving PROGRAF 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 and Oral Suspension) If patients are able to initiate oral therapy, the recommended starting doses should be initiated. PROGRAF Granules for oral suspension or PROGRAF capsules may be taken with or without food. However, since the presence of food affects the bioavailability of PROGRAF, 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 PROGRAF [see Drug Interactions ( 7.2 )]. PROGRAF should not be used simultaneously with cyclosporine. PROGRAF or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated PROGRAF or cyclosporine concentrations, dosing with the other drug usually should be further delayed. Therapeutic drug monitoring (TDM) is recommended for all patients receiving PROGRAF [see Dosage and Administration ( 2.6 )]. 2.2 Dosage Recommendations for Adult Kidney, Liver, Heart, or Lung 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 PROGRAF capsules should be administered no sooner than 6 hours after transplantation in the liver, heart, or lung transplant patients. In kidney transplant patients, the initial dose of PROGRAF capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. The initial oral PROGRAF capsule dosage recommendations for adult patients with kidney, liver, heart, or lung 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 PROGRAF Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults Patient Population PROGRAF 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 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL With MMF/IL-2 receptor antagonist In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL. during month 1-3 and 5-12 ng/mL during month 4-12 [see Clinical Studies ( 14.1 )]. 0.1 mg/kg/day, divided in two doses, administered every 12 hours Month 1-12: 4-11 ng/mL Liver Transplant With corticosteroids only 0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant With azathioprine or MMF 0.075 mg/kg/day, divided in two doses, administered every 12 hours Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL Lung Transplant With azathioprine or MMF 0.075 mg/kg/day Patients with cystic fibrosis may require higher doses due to lower bioavailability [see Clinical Pharmacology ( 12.3 )]. , divided in two doses, administered every 12 hours Month 1-3: 10-15 ng/mL Month 4-12: 8-12 ng/mL Dosage should be titrated based on clinical assessments of rejection and tolerability.
075 mg/kg/day Patients with cystic fibrosis may require higher doses due to lower bioavailability [see Clinical Pharmacology ( 12.3 )]. , divided in two doses, administered every 12 hours Month 1-3: 10-15 ng/mL Month 4-12: 8-12 ng/mL Dosage should be titrated based on clinical assessments of rejection and tolerability. PROGRAF 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 N = 114 African-American 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 In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly. Intravenous Injection PROGRAF 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 PROGRAF capsules should be given 8-12 hours after discontinuing the intravenous infusion. The recommended starting dose of PROGRAF injection is 0.03-0.05 mg/kg/day in kidney or liver transplant, 0.01 mg/kg/day in heart transplant, and 0.01-0.03 mg/kg/day in lung 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 PROGRAF only; while monitoring PROGRAF concentrations in patients receiving PROGRAF 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 PROGRAF injection. Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions ( 5.9 )] . 2.3 Dosage Recommendations for Pediatric Kidney, Liver, Heart, or Lung Transplant Patients Oral formulations (capsules or oral suspension) Pediatric patients, in general, need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole blood trough concentration range are shown in Table 3 . Perform TDM to ensure that patients are within the ranges listed in Table 3 . Table 3. Summary of Initial PROGRAF Capsule and PROGRAF Granules Dosage Recommendations and Whole Blood Trough Concentration Range in Children Patient Population Initial PROGRAF Capsule and PROGRAF Granules Dosing Whole Blood Trough Concentration Range Pediatric kidney transplant patients See Clinical Pharmacology ( 12.3 ) , PROGRAF Granules Pharmacokinetics in Pediatric Patients. 0.3 mg/kg/day capsules or oral suspension, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Pediatric liver transplant patients See Clinical Studies ( 14.2 ) , Liver Transplantation.
transplant patients See Clinical Pharmacology ( 12.3 ) , PROGRAF Granules Pharmacokinetics in Pediatric Patients. 0.3 mg/kg/day capsules or oral suspension, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Pediatric liver transplant patients See Clinical Studies ( 14.2 ) , Liver Transplantation. 0.15-0.2 mg/kg/day capsules or 0.2 mg/kg/day oral suspension, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Pediatric heart transplant patients 0.3 mg/kg/day Dose at 0.1 mg/kg/day if antibody induction treatment is administered. capsules or oral suspension, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Pediatric lung transplant patients 0.3 mg/kg/day , Patients with cystic fibrosis may require higher doses due to lower bioavailability [see Clinical Pharmacology ( 12.3 )]. capsules or oral suspension, divided in two doses, administered every 12 hours Week 1-2: 10-20 ng/mL Week 2 to Month 12: 10-15 ng/mL In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly. For conversion of pediatric patients from PROGRAF Granules to PROGRAF capsules or from PROGRAF capsules to PROGRAF Granules, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration ( 2.6 )]. Intravenous Injection If a patient is unable to receive an oral formulation, the patient may be started on PROGRAF injection. For pediatric liver transplant patients, the intravenous dose is 0.03-0.05 mg/kg/day. 2.4 Dosage Modification for Patients with Renal Impairment Due to its potential for nephrotoxicity, consider dosing PROGRAF at the lower end of the therapeutic dosing range in patients who have received a liver, heart, or lung transplant, and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required. In kidney transplant patients with post-operative oliguria, the initial dose of PROGRAF should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] . 2.5 Dosage Modification for Patients with Hepatic Impairment Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh ≥ 10) may require lower doses of PROGRAF. Close monitoring of blood concentrations is warranted. The use of PROGRAF in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. These patients should be monitored closely, and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )]. 2.6 Therapeutic Drug Monitoring Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments, and compliance. Whole blood trough concentration range can be found in Table 1 .
ic Drug Monitoring Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments, and compliance. Whole blood trough concentration range can be found in Table 1 . Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation. The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure. Methods commonly used for the assay of tacrolimus include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore, assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer, they should be deep frozen at -20°C. One study showed drug recovery > 90% for samples stored at -20°C for 6 months, with reduced recovery observed after 6 months. 2.7 Preparation and Administration Instructions of PROGRAF Injection for Pharmacists Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures 1 [see How Supplied/ Storage and Handling ( 16.4 )] . PROGRAF injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a polyvinyl chloride (PVC) container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Due to the chemical instability of tacrolimus in alkaline media, PROGRAF injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir). 2.8 Preparation and Administration Instructions of PROGRAF Granules Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures 1 [see How Supplied/ Storage and Handling ( 16.4 )] . The required dose for PROGRAF Granules is calculated based on the weight of the patient.
ir or acyclovir). 2.8 Preparation and Administration Instructions of PROGRAF Granules Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures 1 [see How Supplied/ Storage and Handling ( 16.4 )] . The required dose for PROGRAF Granules is calculated based on the weight of the patient. Use the minimum whole number of packets that corresponds to the required morning or evening dose. If the morning or evening dose is not covered by the whole number of packets, use one additional 0.2 mg packet to round up the dose. Do not use tubing, syringes and other equipment (cups) containing PVC to prepare or administer tacrolimus products. Do not sprinkle PROGRAF Granules on food. Prepare and administer PROGRAF Granules as follows: • To prepare the dose, empty the entire contents of each PROGRAF Granules packet into a glass cup. Check for any remaining granules in the packet(s) and empty these into the cup. • Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the cup containing the PROGRAF Granules. • Mix and administer the entire contents of the cup. The granules will not completely dissolve. The suspension should be given immediately after preparation. • For younger patients, the suspension can be drawn up via a non-PVC oral syringe that will be dispensed with the prescription. • The cup or syringe should be rinsed with the same quantity of water (15 to 30 milliliters) and given to the patient to ensure all of the medication is taken. • The pharmacy must dispense with the Instructions for Use. Alert the patient to read the Instructions for Use.
3 DOSAGE FORMS AND STRENGTHS PROGRAF is available in the following dosage forms and strengths: Capsules Oblong, hard capsule for oral administration contains anhydrous tacrolimus USP as follows: • 0.5 mg, light-yellow color, imprinted in red “0.5 mg” on the capsule cap and “ 607” on capsule body • 1 mg, white color, imprinted in red “1 mg” on the capsule cap and “ 617” on capsule body • 5 mg, grayish-red color, imprinted with white “5 mg” on the capsule cap and “ 657” on capsule body Injection 1 mL ampule for intravenous infusion contains anhydrous tacrolimus USP, 5 mg/mL For Oral Suspension Unit-dose packets with white granules for oral suspension contains anhydrous tacrolimus USP: • 0.2 mg • 1 mg • Capsules: 0.5 mg, 1 mg and 5 mg ( 3 ) • Injection: 5 mg/mL ( 3 ) • For oral suspension: 0.2 mg, 1 mg unit-dose packets containing granules ( 3 ) Letter f logo Letter f logo Letter f logo
<table width="100%"><col width="19%"/><col width="81%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Capsules</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Oblong, hard capsule for oral administration contains anhydrous tacrolimus USP as follows: </paragraph><paragraph> • 0.5 mg, light-yellow color, imprinted in red “0.5 mg” on the capsule cap and “<renderMultiMedia ID="id-823118709" referencedObject="ID_48d4dcca-8f1f-4f25-83b6-cb1563890984"/>607” on capsule body</paragraph><paragraph> • 1 mg, white color, imprinted in red “1 mg” on the capsule cap and “<renderMultiMedia ID="id1908573719" referencedObject="ID_0cc8d500-6770-4356-9635-ab0238848b9c"/>617” on capsule body</paragraph><paragraph> • 5 mg, grayish-red color, imprinted with white “5 mg” on the capsule cap and “<renderMultiMedia ID="id-2127991191" referencedObject="ID_9168b597-c79b-45ae-9d65-10ee8eb16bf3"/>657” on capsule body</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 mL ampule for intravenous infusion contains anhydrous tacrolimus USP, 5 mg/mL </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>For Oral Suspension</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Unit-dose packets with white granules for oral suspension contains anhydrous tacrolimus USP:</paragraph><list listType="unordered"><item><caption>•</caption>0.2 mg</item><item><caption>•</caption>1 mg</item></list></td></tr></tbody></table>
4 CONTRAINDICATIONS PROGRAF is contraindicated in patients with a hypersensitivity to tacrolimus. PROGRAF 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 )] . • Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 )
5 WARNINGS AND PRECAUTIONS • Not Interchangeable with Extended-Release Tacrolimus Products - Medication Errors: Instruct patients or caregivers to recognize the appearance of PROGRAF capsules. ( 5.3 ) • New Onset Diabetes After Transplant: Monitor blood glucose. ( 5.4 ) • Nephrotoxicity (acute and/or chronic): Reduce the dose; use caution with other nephrotoxic drugs. ( 5.5 ) • Neurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue PROGRAF. ( 5.6 ) • Hyperkalemia: Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia. ( 5.7 ) • Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions. ( 5.8 ) • Anaphylactic Reactions with IV formulation: Observe patients receiving PROGRAF injection for signs and symptoms of anaphylaxis. ( 5.9 ) • Not recommended for use with sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions. ( 5.10 ) • Myocardial Hypertrophy: Consider dose reduction/discontinuation. ( 5.13 ) • Immunizations: Avoid live vaccines. ( 5.14 ) • Pure Red Cell Aplasia: Consider discontinuation of PROGRAF. ( 5.15 ) • Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.16 ) 5.1 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including PROGRAF, are at increased 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. As usual for patients with increased risk for skin cancer, examine patients for skin changes; exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein-Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment. 5.2 Serious Infections Patients receiving immunosuppressants, including PROGRAF, are at increased 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 (PVAN), mostly due to BK virus infection • JC virus-associated progressive multifocal leukoencephalopathy (PML) • Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing 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 )].
ransplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing 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 Not Interchangeable with Extended-Release Tacrolimus Products - Medication Errors Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or overexposure to tacrolimus. PROGRAF is not interchangeable or substitutable for tacrolimus extended-release products. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision. Instruct patients and caregivers to recognize the appearance of PROGRAF dosage forms [see Dosage Forms and Strengths ( 3 )] and to confirm with the healthcare provider if a different product is dispensed . 5.4 New Onset Diabetes After Transplant PROGRAF was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, heart, or lung transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using PROGRAF [see Adverse Reactions ( 6.1 )] . 5 .5 Nephrotoxicity due to PROGRAF and Drug Interactions PROGRAF, 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. Nephrotoxicity was reported in clinical trials [see Adverse Reactions ( 6.1 )] . 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 PROGRAF 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 doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions ( 7.2 )] . 5.6 Neurotoxicity PROGRAF 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 PROGRAF if neurotoxicity occurs. 5.7 Hyperkalemia Hyperkalemia has been reported with PROGRAF use. Serum potassium levels should be monitored.
sociated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of PROGRAF if neurotoxicity occurs. 5.7 Hyperkalemia Hyperkalemia has been reported with PROGRAF use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during PROGRAF therapy [see Adverse Reactions ( 6.1 )] . Monitor serum potassium levels periodically during treatment. 5.8 Hypertension Hypertension is a common adverse effect of PROGRAF therapy and may require antihypertensive therapy [see Adverse Reactions ( 6.1 )]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions ( 5.7 )] . Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of PROGRAF [see Drug Interactions ( 7.2 )]. 5.9 Anaphylactic Reactions with PROGRAF Injection Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including PROGRAF, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. PROGRAF injection should be reserved for patients who are unable to take PROGRAF orally. Monitor patients for anaphylaxis when using the intravenous route of administration [see Dosage and Administration ( 2.1 )]. 5 .10 Not Recommended for Use with Sirolimus PROGRAF is not recommended for use with sirolimus: • The use of sirolimus with PROGRAF in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT), and is not recommended. • The use of sirolimus (2 mg per day) with PROGRAF in heart transplant patients in a U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies ( 14.3 )] . • The use of sirolimus with PROGRAF may increase the risk of thrombotic microangiopathy [see Warnings and Precautions ( 5.16 )] . 5.11 Interactions with CYP3A4 Inhibitors and Inducers When co-administering PROGRAF with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of PROGRAF and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions ( 7.2 )] . 5.12 QT Prolongation PROGRAF may prolong the QT/QTc interval and may cause Torsades de pointes . Avoid PROGRAF in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.
king certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. When co-administering PROGRAF with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in PROGRAF dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of PROGRAF with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions ( 7.2 )] . 5.13 Myocardial Hypertrophy Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving PROGRAF therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of PROGRAF should be considered [see Adverse Reactions ( 6.2 )] . 5.14 Immunizations Whenever possible, administer the complete complement of vaccines before transplantation and treatment with PROGRAF. The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: 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 PROGRAF. 5.15 Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of PROGRAF should be considered [see Adverse Reactions ( 6.2 )] . 5.16 Thrombotic Microangiopathy (Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura) Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with PROGRAF. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA. In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA. 5.17 Cannabidiol Drug Interactions When cannabidiol and PROGRAF are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of PROGRAF should be considered as needed when PROGRAF is co-administered with cannabidiol [ see Dosage and Administration ( 2.2 , 2.6 ) and Drug Interactions ( 7.3 ) ] .
6 ADVERSE REACTIONS The following serious and otherwise important 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 )] • New Onset Diabetes After Transplant [see Warnings and Precautions ( 5.4 )] • Nephrotoxicity [see Warnings and Precautions ( 5.5 )] • Neurotoxicity [see Warnings and Precautions ( 5.6 )] • Hyperkalemia [see Warnings and Precautions ( 5.7 )] • Hypertension [see Warnings and Precautions ( 5.8 )] • Anaphylactic Reactions with PROGRAF Injection [see Warnings and Precautions ( 5.9 )] • Myocardial Hypertrophy [see Warnings and Precautions ( 5.13 )] • Pure Red Cell Aplasia [see Warnings and Precautions ( 5.15 )] • Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions ( 5.16 )] The most common adverse reactions (≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia. ( 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 Transplantation The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression. PROGRAF-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received PROGRAF-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on PROGRAF and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below. The most common adverse reactions (≥ 30%) observed in PROGRAF-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.
ain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with PROGRAF in conjunction with azathioprine are presented below: Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF in Conjunction with Azathioprine (AZA) PROGRAF/AZA (N = 205) Cyclosporine/AZA (N = 207) Nervous System Tremor 54% 34% Headache 44% 38% Insomnia 32% 30% Paresthesia 23% 16% Dizziness 19% 16% Gastrointestinal Diarrhea 44% 41% Nausea 38% 36% Constipation 35% 43% Vomiting 29% 23% Dyspepsia 28% 20% Cardiovascular Hypertension 50% 52% Chest Pain 19% 13% Urogenital Creatinine Increased 45% 42% Urinary Tract Infection 34% 35% Metabolic and Nutritional Hypophosphatemia 49% 53% Hypomagnesemia 34% 17% Hyperlipemia 31% 38% Hyperkalemia 31% 32% Diabetes Mellitus 24% 9% Hypokalemia 22% 25% Hyperglycemia 22% 16% Edema 18% 19% Hemic and Lymphatic Anemia 30% 24% Leukopenia 15% 17% Miscellaneous Infection 45% 49% Peripheral Edema 36% 48% Asthenia 34% 30% Abdominal Pain 33% 31% Pain 32% 30% Fever 29% 29% Back Pain 24% 20% Respiratory System Dyspnea 22% 18% Cough Increased 18% 15% Musculoskeletal Arthralgia 25% 24% Skin Rash 17% 12% Pruritus 15% 7% Two trials were conducted for PROGRAF-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received PROGRAF (Group C, n = 403), or one of two cyclosporine (CsA) regimens (Group A, n = 384 and Group B, n = 408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with PROGRAF in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below: Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with PROGRAF in Conjunction with MMF (Study 1) PROGRAF (Group C) (N = 403) Cyclosporine (Group A) (N = 384) Cyclosporine (Group B) (N = 408) Diarrhea 25% 16% 13% Urinary Tract Infection 24% 28% 24% Anemia 17% 19% 17% Hypertension 13% 14% 12% Leukopenia 13% 10% 10% Edema Peripheral 11% 12% 13% Hyperlipidemia 10% 15% 13% Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil In the U.S. trial (Study 2) with PROGRAF-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received PROGRAF (n = 212) or cyclosporine (n = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with PROGRAF in conjunction with MMF in Study 2 are presented below: Table 6.
d the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with PROGRAF in conjunction with MMF in Study 2 are presented below: Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF in Conjunction with MMF (Study 2) PROGRAF/MMF Cyclosporine/MMF (N = 212) (N = 212) Gastrointestinal Disorders Diarrhea 44% 26% Nausea 39% 47% Constipation 36% 41% Vomiting 26% 25% Dyspepsia 18% 15% Injury, Poisoning, and Procedural Complications Post-Procedural Pain 29% 27% Incision Site Complication 28% 23% Graft Dysfunction 24% 18% Metabolism and Nutrition Disorders Hypomagnesemia 28% 22% Hypophosphatemia 28% 21% Hyperkalemia 26% 19% Hyperglycemia 21% 15% Hyperlipidemia 18% 25% Hypokalemia 16% 18% Nervous System Disorders Tremor 34% 20% Headache 24% 25% Blood and Lymphatic System Disorders Anemia 30% 28% Leukopenia 16% 12% Miscellaneous Edema Peripheral 35% 46% Hypertension 32% 35% Insomnia 30% 21% Urinary Tract Infection 26% 22% Blood Creatinine Increased 23% 23% Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.” Liver Transplantation There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70); the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%), and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%), and Other (2%). The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥ 15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation. The most common adverse reactions (≥ 40%) observed in PROGRAF-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of PROGRAF and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving PROGRAF in the U.S. and European randomized trials. Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF U.S.
adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving PROGRAF in the U.S. and European randomized trials. Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF U.S. TRIAL EUROPEAN TRIAL PROGRAF (N = 250) Cyclosporine/ AZA (N = 250) PROGRAF (N = 264) Cyclosporine/ AZA (N = 265) Nervous System Headache 64% 60% 37% 26% Insomnia 64% 68% 32% 23% Tremor 56% 46% 48% 32% Paresthesia 40% 30% 17% 17% Gastrointestinal Diarrhea 72% 47% 37% 27% Nausea 46% 37% 32% 27% LFT Abnormal 36% 30% 6% 5% Anorexia 34% 24% 7% 5% Vomiting 27% 15% 14% 11% Constipation 24% 27% 23% 21% Cardiovascular Hypertension 47% 56% 38% 43% Urogenital Kidney Function Abnormal 40% 27% 36% 23% Creatinine Increased 39% 25% 24% 19% BUN Increased 30% 22% 12% 9% Oliguria 18% 15% 19% 12% Urinary Tract Infection 16% 18% 21% 19% Metabolic and Nutritional Hypomagnesemia 48% 45% 16% 9% Hyperglycemia 47% 38% 33% 22% Hyperkalemia 45% 26% 13% 9% Hypokalemia 29% 34% 13% 16% Hemic and Lymphatic Anemia 47% 38% 5% 1% Leukocytosis 32% 26% 8% 8% Thrombocytopenia 24% 20% 14% 19% Miscellaneous Pain 63% 57% 24% 22% Abdominal Pain 59% 54% 29% 22% Asthenia 52% 48% 11% 7% Fever 48% 56% 19% 22% Back Pain 30% 29% 17% 17% Ascites 27% 22% 7% 8% Peripheral Edema 26% 26% 12% 14% Respiratory System Pleural Effusion 30% 32% 36% 35% Dyspnea 29% 23% 5% 4% Atelectasis 28% 30% 5% 4% Skin and Appendages Pruritus 36% 20% 15% 7% Rash 24% 19% 10% 4% Table 8. Pediatric Liver Transplantation: Adverse Reactions Occurring in > 10% of Patients Treated with PROGRAF Granules (STUDY 01-13) PROGRAF Granules (N = 91) Cyclosporine (N = 90) Body as a Whole Fever 46% 51% Infection 25% 29% Sepsis 22% 20% CMV Infection 15% 24% EBV Infection 26% 11% Ascites 17% 20% Peritonitis 12% 7% Cardiovascular System Hypertension 39% 47% Digestive System Liver Function Tests Abnormal 37% 28% Diarrhea 26% 26% Vomiting 15% 13% Gastrointestinal Hemorrhage 11% 12% Bile Duct Disorder 12% 8% Gastroenteritis 12% 4% Hemic and Lymphatic System Anemia 29% 19% Metabolic and Nutritional Disorders Hypomagnesemia 40% 29% Acidosis 26% 17% Hyperkalemia 12% 10% Respiratory System Pleural Effusion 22% 19% Bronchitis 11% 8% Urogenital System Kidney Function Abnormal 13% 14% Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “ Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.” Heart Transplantation The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with PROGRAF (n = 157) or cyclosporine (n = 157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%). The most common adverse reactions (≥ 15%) observed in PROGRAF-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial. Adverse reactions in heart transplant patients in the European trial are presented below: Table 9.
ry tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial. Adverse reactions in heart transplant patients in the European trial are presented below: Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF in Conjunction with Azathioprine (AZA) PROGRAF/AZA (N = 157) Cyclosporine/AZA (N = 157) Cardiovascular System Hypertension 62% 69% Pericardial Effusion 15% 14% Body as a Whole CMV Infection 32% 30% Infection 24% 21% Metabolic and Nutritional Disorders Diabetes Mellitus 26% 16% Hyperglycemia 23% 17% Hyperlipemia 18% 27% Hemic and Lymphatic System Anemia 50% 36% Leukopenia 48% 39% Urogenital System Kidney Function Abnormal 56% 57% Urinary Tract Infection 16% 12% Respiratory System Bronchitis 17% 18% Nervous System Tremor 15% 6% In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and PROGRAF in combination with sirolimus (n=109), PROGRAF in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%). Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with PROGRAF and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%) , hypertriglyceridemia (65%), anemia (hemoglobin < 10.0 g/dL) (65%), fasting blood glucose > 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs < 3000 cells/mcL (34%), serious bacterial infections (30%), magnesium < 1.2 mEq/L (24%), platelet count < 75,000 cells/mcL (19%), and other opportunistic infections (15%). Other targeted treatment-emergent adverse reactions in PROGRAF-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.” New Onset Diabetes After Transplant Kidney Transplantation New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥ 126 mg/dL, HbA 1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the PROGRAF-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus ( Table 10 ) [see Clinical Studies ( 14.1 )] . Table 10.
26 mg/dL, HbA 1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the PROGRAF-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus ( Table 10 ) [see Clinical Studies ( 14.1 )] . Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2) Parameter Treatment Group PROGRAF/MMF (N = 212) NEORAL/MMF (N = 212) NODAT 112/150 (75%) 93/152 (61%) Fasting Plasma Glucose ≥ 126 mg/dL 96/150 (64%) 80/152 (53%) HbA 1C ≥ 6% 59/150 (39%) 28/152 (18%) Insulin Use ≥ 30 days 9/150 (6%) 4/152 (3%) Oral Hypoglycemic Use 15/150 (10%) 5/152 (3%) In early trials of PROGRAF, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of “use of insulin for 30 or more consecutive days with < 5-day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14 . PTDM was reported in 20% of PROGRAF/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial ( Table 11 ). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM ( Table 12 ). Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA) Status of PTDM Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. PROGRAF/AZA CsA/AZA Patients without pre-transplant history of diabetes mellitus 151 151 New onset PTDM , 1 st Year 30/151 (20%) 6/151 (4%) Still insulin-dependent at one year in those without prior history of diabetes 25/151 (17%) 5/151 (3%) New onset PTDM post 1 year 1 0 Patients with PTDM at 2 years 16/151 (11%) 5/151 (3%) Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial Patient Race Patients Who Developed PTDM Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. PROGRAF Cyclosporine African-American 15/41 (37%) 3 (8%) Hispanic 5/17 (29%) 1 (6%) Caucasian 10/82 (12%) 1 (1%) Other 0/11 (0%) 1 (10%) Total 30/151 (20%) 6 (4%) Liver Transplantation Insulin-dependent PTDM was reported in 18% and 11% of PROGRAF-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively ( Table 13 ). Hyperglycemia was associated with the use of PROGRAF in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions ( 6.1 )]. Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients Status of PTDM Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. US Trial European Trial PROGRAF Cyclosporine PROGRAF Cyclosporine Patients at risk Patients without pre-transplant history of diabetes mellitus.
DM Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. US Trial European Trial PROGRAF Cyclosporine PROGRAF Cyclosporine Patients at risk Patients without pre-transplant history of diabetes mellitus. 239 236 239 249 New Onset PTDM 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) Heart Transplantation Insulin-dependent PTDM was reported in 13% and 22% of PROGRAF-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively ( Table 14 ). Hyperglycemia, defined as two fasting plasma glucose levels ≥ 126 mg/dL, was reported with the use of PROGRAF plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions ( 6.1 )]. Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients Status of PTDM Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. US Trial European Trial PROGRAF/MMF Cyclosporine/MMF PROGRAF/AZA Cyclosporine/AZA Patients at risk Patients without pre-transplant history of diabetes mellitus. 75 83 132 138 New Onset PTDM 10 (13%) 6 (7%) 29 (22%) 5 (4%) Patients still on insulin at 1 year 7-12 months for the U.S. trial. 7 (9%) 1 (1%) 24 (18%) 4 (3%) Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.
nths for the U.S. trial. 7 (9%) 1 (1%) 24 (18%) 4 (3%) Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials. • Nervous System: Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired • Special Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitus • Gastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis • Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation • Urogenital: Acute kidney failure , albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis • Metabolic/Nutritional: Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gain • Endocrine: Cushing’s syndrome • Hemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased • Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer • Musculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis • Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration • Skin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweating Lung Transplantation Adverse reactions in lung transplant patients were similar to those in kidney, liver, or heart transplant patients treated with PROGRAF [see Adverse Reactions ( 6.2 )]. 6.2 Postmarketing Experience The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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.
ing Experience The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug. Other reactions include: • Cardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsades de pointes , venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy • Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease • Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia, thrombotic microangiopathy • Infections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; polyoma virus-associated nephropathy (PVAN) including graft loss • Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased • Miscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction • Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) • Nervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope • Respiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure • Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis • Special Senses: Blindness, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia • Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome Postmarketing Adverse Reactions in Lung Transplantation Based on U.S. Scientific Registry of Transplant Recipients (SRTR) data, published clinical trials, and postmarketing reports, the safety profile for lung transplant patients treated with PROGRAF is consistent with the safety profile in kidney, liver, and heart transplant patients treated with PROGRAF. The primary adverse reactions described include renal dysfunction, infection, diabetes, gastrointestinal disturbances (e.g., diarrhea), hypertension, and neurological events (e.g., tremor). As expected, lung transplant patients have a higher incidence of pulmonary complications (e.g., pneumonia, bronchiolitis obliterans syndrome) than other solid organ transplant patients, which is in part due to the underlying disease and to the nature of the transplanted organ.
<table cellpadding="5.75pt" width="100%"><caption>Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF in Conjunction with Azathioprine (AZA)</caption><col width="53%"/><col width="24%"/><col width="23%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">PROGRAF/AZA</content> <content styleCode="bold">(N = 205)</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N = 207)</content></th></tr></thead><tbody><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Tremor </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>54%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>44%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Paresthesia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dizziness</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>44%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>41%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>43%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule L
lign="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>43%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule L rule Botrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspepsia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>50%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>52%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Chest Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Creatinine Increased </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Urinary Tract Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypophosphatemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>49%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>53%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypomagnesemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperlipemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperkalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diabetes Mellitus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botru
eCode="Rrule Lrule Botrule " valign="top"><paragraph> Diabetes Mellitus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botru le " valign="top"><paragraph> Hypokalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperglycemia </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Edema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Miscellaneous</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>49%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Peripheral Edema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Asthenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Abdominal Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>33%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fever</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top
="Rrule Lrule Botrule " valign="top"><paragraph> Fever</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top "><paragraph> Back Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Cough Increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Arthralgia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rash</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7%</paragraph></td></tr></tbody></table>
agraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7%</paragraph></td></tr></tbody></table> <table ID="_Refid_7823f154-1182-49e2-8669-f527f5f64" width="100%"><caption>Table 5.
agraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7%</paragraph></td></tr></tbody></table> <table ID="_Refid_7823f154-1182-49e2-8669-f527f5f64" width="100%"><caption>Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with PROGRAF in Conjunction with MMF (Study 1)</caption><col width="41%"/><col width="20%"/><col width="19%"/><col width="19%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold"> </content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">PROGRAF</content> <content styleCode="bold">(Group C)</content></paragraph><paragraph><content styleCode="bold">(N = 403)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine</content> <content styleCode="bold">(Group A)</content></paragraph><paragraph><content styleCode="bold">(N = 384)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine</content> <content styleCode="bold">(Group B)</content></paragraph><paragraph><content styleCode="bold">(N = 408)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Urinary Tract Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Edema Peripheral</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrul
d align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrul e Botrule " valign="top"><paragraph> Hyperlipidemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil</paragraph></td></tr></tbody></table> <table ID="_Refid_cd95fd71-359e-478e-b210-214ecde7d" width="100%"><caption>Table 6.
e Botrule " valign="top"><paragraph> Hyperlipidemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil</paragraph></td></tr></tbody></table> <table ID="_Refid_cd95fd71-359e-478e-b210-214ecde7d" width="100%"><caption>Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF in Conjunction with MMF (Study 2)</caption><col width="54%"/><col width="22%"/><col width="24%"/><thead><tr><th align="left" styleCode="Rrule Lrule Toprule " valign="top"><content styleCode="bold"> </content></th><th align="center" styleCode="Rrule Lrule Toprule " valign="middle"><content styleCode="bold">PROGRAF/MMF</content></th><th align="center" styleCode="Rrule Lrule Toprule " valign="middle"><content styleCode="bold">Cyclosporine/MMF</content></th></tr><tr><th align="left" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold"> </content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">(N = 212)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">(N = 212)</content></th></tr></thead><tbody><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td><td styleCode="Botrule " valign="middle"/><td styleCode="Rrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>44%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>26%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>39%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>47%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>41%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspepsia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>15%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Injury, Poisoning, and Procedural Complications</content></paragraph></td><td styleCode="Botrule " valign="middle"/><td styleCode="Rrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Post-Procedural Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Incision Site Complication</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>23%</paragraph></td></tr
/td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Incision Site Complication</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>23%</paragraph></td></tr ><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Graft Dysfunction</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td><td styleCode="Botrule " valign="middle"/><td styleCode="Rrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypomagnesemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypophosphatemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>21%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperkalemia </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperglycemia </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>21%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>15%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperlipidemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypokalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td><td styleCode="Botrule " valign="middle"/><td styleCode="Rrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Tremor </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>20%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Blood and Lymphatic System Disorders</content></paragraph></td><td styleCode="Botrule " valign="middle"/><td styleCode="Rrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia</paragraph></td><td ali
Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Blood and Lymphatic System Disorders</content></paragraph></td><td styleCode="Botrule " valign="middle"/><td styleCode="Rrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia</paragraph></td><td ali gn="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>28%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Miscellaneous</content></paragraph></td><td styleCode="Botrule " valign="middle"/><td styleCode="Rrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Edema Peripheral</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>35%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>46%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>35%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>21%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Urinary Tract Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Blood Creatinine Increased</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>23%</paragraph></td></tr></tbody></table>
styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Blood Creatinine Increased</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>23%</paragraph></td></tr></tbody></table> <table ID="_Refid_be0f1c75-3b15-4462-b968-69c0c86dc" cellpadding="5.75pt" width="100%"><caption>Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF </caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="19%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">U.S.
ROGRAF </caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="19%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">U.S. TRIAL</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">EUROPEAN TRIAL</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">PROGRAF</content> <content styleCode="bold">(N = 250)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">Cyclosporine/</content> <content styleCode="bold">AZA</content> <content styleCode="bold">(N = 250)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">PROGRAF</content> <content styleCode="bold">(N = 264)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">Cyclosporine/</content> <content styleCode="bold">AZA</content> <content styleCode="bold">(N = 265)</content></th></tr></thead><tbody><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>64%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>64%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>68%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Tremor</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>46%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Paresthesia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>72%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top
rule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>72%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top "><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>46%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> LFT Abnormal</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anorexia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>43%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Kidney Function Abnormal</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40%
span="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Kidney Function Abnormal</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Creatinine Increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>39%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> BUN Increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Oliguria</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Urinary Tract Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypomagnesemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperglycemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>33%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperkalemia</paragraph></td><td align="cen
aragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>33%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperkalemia</paragraph></td><td align="cen ter" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypokalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukocytosis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Thrombocytopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Miscellaneous</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>63%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>57%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Abdominal Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>59%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>54%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrul
d align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>59%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>54%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrul e Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Asthenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>52%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fever</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Back Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Ascites</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Peripheral Edema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pleural Effusion</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="ce
nea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="ce nter" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Atelectasis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and Appendages</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Rash</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table> <table ID="_RefID0EXHCI" width="100%"><caption>Table 8.
nter" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Atelectasis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and Appendages</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Rash</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table> <table ID="_RefID0EXHCI" width="100%"><caption>Table 8. Pediatric Liver Transplantation: Adverse Reactions Occurring in > 10% of Patients Treated with PROGRAF Granules (STUDY 01-13)</caption><col width="40%"/><col width="32%"/><col width="28%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">PROGRAF Granules</content> <content styleCode="bold">(N = 91)</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Cyclosporine</content> <content styleCode="bold">(N = 90)</content></th></tr></thead><tbody><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fever</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>46%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>51%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Sepsis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> CMV Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> EBV Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Ascites</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Peritonitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>39%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Digestive System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Liver Function
nter" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Digestive System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Liver Function Tests Abnormal</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Gastrointestinal Hemorrhage</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Bile Duct Disorder</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Gastroenteritis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypomagnesemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Acidosis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperkalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pleural Effusion</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " va
aph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pleural Effusion</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " va lign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Bronchitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital System</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Kidney Function Abnormal</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>14%</paragraph></td></tr></tbody></table> <table ID="_Refid_e2713aef-d0f1-4aa7-9018-6c377380b" width="100%"><caption>Table 9.
lign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Bronchitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital System</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Kidney Function Abnormal</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>14%</paragraph></td></tr></tbody></table> <table ID="_Refid_e2713aef-d0f1-4aa7-9018-6c377380b" width="100%"><caption>Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF in Conjunction with Azathioprine (AZA)</caption><col width="46%"/><col width="28%"/><col width="26%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">PROGRAF/AZA</content> <content styleCode="bold">(N = 157)</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N = 157)</content></th></tr></thead><tbody><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>62%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>69%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pericardial Effusion</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> CMV Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diabetes Mellitus </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperglycemia </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperlipemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " vali
ph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " vali gn="top"><paragraph>50%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>39%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Kidney Function Abnormal </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>57%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Urinary Tract Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Bronchitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Tremor </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6%</paragraph></td></tr></tbody></table>
ragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Tremor </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6%</paragraph></td></tr></tbody></table> <table ID="_Ref514839046" width="101.54%"><caption>Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)</caption><col width="33%"/><col width="33%"/><col width="33%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Parameter</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Treatment Group</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">PROGRAF/MMF</content> <content styleCode="bold">(N = 212)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">NEORAL/MMF</content> <content styleCode="bold">(N = 212)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NODAT</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>112/150 (75%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>93/152 (61%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fasting Plasma Glucose ≥ 126 mg/dL</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>96/150 (64%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>80/152 (53%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> HbA<sub>1C </sub>≥ 6%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>59/150 (39%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>28/152 (18%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Insulin Use ≥ 30 days</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9/150 (6%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4/152 (3%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Oral Hypoglycemic Use</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15/150 (10%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5/152 (3%)</paragraph></td></tr></tbody></table>
tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Oral Hypoglycemic Use</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15/150 (10%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5/152 (3%)</paragraph></td></tr></tbody></table> <table ID="_Ref519160382" width="100%"><caption>Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)</caption><col width="58%"/><col width="23%"/><col width="19%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Status of PTDM</content><footnote ID="_Ref519160542">Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</footnote></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">PROGRAF/AZA</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">CsA/AZA</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Patients without pre-transplant history of diabetes mellitus</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>151</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>151</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> New onset PTDM<footnoteRef IDREF="_Ref519160542"/>, 1<sup>st</sup> Year</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>30/151 (20%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6/151 (4%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Still insulin-dependent at one year in those without prior history of diabetes</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>25/151 (17%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5/151 (3%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> New onset PTDM<footnoteRef IDREF="_Ref519160542"/> post 1 year</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Patients with PTDM<footnoteRef IDREF="_Ref519160542"/> at 2 years</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>16/151 (11%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5/151 (3%)</paragraph></td></tr></tbody></table>
gn="top"><paragraph> Patients with PTDM<footnoteRef IDREF="_Ref519160542"/> at 2 years</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>16/151 (11%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5/151 (3%)</paragraph></td></tr></tbody></table> <table ID="_Ref514839134" width="100%"><caption>Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial</caption><col width="28%"/><col width="36%"/><col width="36%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Patient Race</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">Patients Who Developed PTDM</content><footnote ID="_Refid-a9cb3ff7-b459-46e2-b28d-ae27cd9f4">Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</footnote></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">PROGRAF</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Cyclosporine</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> African-American</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15/41 (37%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3 (8%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hispanic</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5/17 (29%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1 (6%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Caucasian</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10/82 (12%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1 (1%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Other</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0/11 (0%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1 (10%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Total</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>30/151 (20%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6 (4%)</paragraph></td></tr></tbody></table>
aragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Total</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>30/151 (20%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6 (4%)</paragraph></td></tr></tbody></table> <table ID="_Ref514839188" width="100%"><caption>Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients</caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Status of PTDM</content><footnote ID="_Refid-79a1ec63-01fb-48f8-b5ff-5d39658d9">Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</footnote></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">US Trial</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">European Trial</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">PROGRAF</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Cyclosporine</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">PROGRAF</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Cyclosporine</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Patients at risk<footnote ID="_Ref54344531">Patients without pre-transplant history of diabetes mellitus.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>239</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>236</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>239</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>249</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>New Onset PTDM<footnoteRef IDREF="_Refid-79a1ec63-01fb-48f8-b5ff-5d39658d9"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>42 (18%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>30 (13%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26 (11%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12 (5%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Patients still on insulin at 1 year</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>23 (10%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>19 (8%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>18 (8%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 (2%)</paragraph></td></tr></tbody></table>
aph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>19 (8%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>18 (8%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 (2%)</paragraph></td></tr></tbody></table> <table ID="_Ref519161326" width="100%"><caption>Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients</caption><col width="19%"/><col width="20%"/><col width="21%"/><col width="21%"/><col width="20%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Status of PTDM</content><footnote ID="_Ref519161174">Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</footnote></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">US Trial</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">European Trial</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">PROGRAF/MMF</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Cyclosporine/MMF</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">PROGRAF/AZA</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Cyclosporine/AZA</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Patients at risk<footnote ID="_Ref519161225">Patients without pre-transplant history of diabetes mellitus.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>75</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>83</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>132</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>138</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>New Onset PTDM<footnoteRef IDREF="_Ref519161174"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 (13%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 (7%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>29 (22%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 (4%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Patients still on insulin at 1 year<footnote ID="_Ref519161243">7-12 months for the U.S. trial.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>7 (9%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 (1%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>24 (18%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 (3%)</paragraph></td></tr></tbody></table>
7 DRUG INTERACTIONS • Mycophenolic Acid Products: Can increase MPA exposure after crossover from cyclosporine to PROGRAF; 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 PROGRAF should be considered when PROGRAF is co-administered with cannabidiol ( 5.17 , 7.3 ). 7.1 Mycophenolic Acid When PROGRAF is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with PROGRAF 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 PROGRAF Table 15 displays the effects of other drugs on PROGRAF. Table 15. Effects of Other Drugs/Substances on PROGRAF PROGRAF 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 ( 5.6 , 5.11 , 5.12 )] . Avoid grapefruit or grapefruit juice. 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 ( 5.11 )] . Increase PROGRAF dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration ( 2.2 , 2.6 ) 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 ( 5.6 , 5.11 , 5.12 )] .
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 PROGRAF 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 PROGRAF 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 PROGRAF 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 PROGRAF 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 PROGRAF 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 PROGRAF 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 PROGRAF are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of PROGRAF should be considered as needed when PROGRAF is co-administered with cannabidiol [see Dosage and Administration ( 2.2 , 2.6 ) and Warnings and Precautions ( 5.17 ) ] .
<table ID="_Ref514855204" width="97.64%"><caption>Table 15. Effects of Other Drugs/Substances on PROGRAF<footnote ID="_Ref536794849">PROGRAF dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures <content styleCode="italics">[see <linkHtml href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</linkHtml> (<linkHtml href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</linkHtml>)]</content>, literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status.</footnote></caption><col width="36%"/><col width="35%"/><col width="29%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Drug/Substance Class or Name</content></th><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Drug Interaction Effect</content></th><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Recommendations</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Grapefruit or grapefruit juice<footnote ID="_Ref536794614">High dose or double strength grapefruit juice is a <content styleCode="italics">strong</content> CYP3A inhibitor; low dose or single strength grapefruit juice is a <content styleCode="italics">moderate</content> CYP3A inhibitor.</footnote></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see <linkHtml href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</linkHtml> (<linkHtml href="#i4i_section_id_30c689c5-c4ac-4245-b169-23d784fda7f3">5.6</linkHtml>, <linkHtml href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</linkHtml>, <linkHtml href="#ID_d05977d5-ff84-489b-bffa-eebc1127623e">5.12</linkHtml>)]</content>.</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Avoid grapefruit or grapefruit juice.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Strong CYP3A Inducers<footnote ID="_Ref536794625">Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting <content styleCode="italics">in vitro</content> CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate).</footnote>:</paragraph><list listType="unordered"><item><caption> </caption>Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s wort</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection <content styleCode="italics">[see <linkHtml href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</linkHtml> (<linkHtml href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</linkHtml>)]</content>.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Increase PROGRAF dose and monitor tacrolimus whole blood trough concentrations <content styleCode="italics">[see <linkHtml href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-
D_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</linkHtml>)]</content>.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Increase PROGRAF dose and monitor tacrolimus whole blood trough concentrations <content styleCode="italics">[see <linkHtml href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb- bb6550f68aac">Dosage and Administration</linkHtml> (<linkHtml href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</linkHtml>, <linkHtml href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</linkHtml>) and <linkHtml href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</linkHtml> (<linkHtml href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Strong CYP3A Inhibitors<footnoteRef IDREF="_Ref536794625"/>:</paragraph><list listType="unordered"><item><caption> </caption>Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, <content styleCode="italics">Schisandra sphenanthera </content>extracts</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).
azodone, letermovir, <content styleCode="italics">Schisandra sphenanthera </content>extracts</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>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<content styleCode="italics"> [see <linkHtml href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</linkHtml> (<linkHtml href="#i4i_section_id_30c689c5-c4ac-4245-b169-23d784fda7f3">5.6</linkHtml>, <linkHtml href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</linkHtml>, <linkHtml href="#ID_d05977d5-ff84-489b-bffa-eebc1127623e">5.12</linkHtml>)]</content>.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Reduce PROGRAF dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations <content styleCode="italics">[see <linkHtml href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</linkHtml> (<linkHtml href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</linkHtml>, <linkHtml href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</linkHtml>) and <linkHtml href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</linkHtml> (<linkHtml href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</linkHtml>)]</content>.
>2.2</linkHtml>, <linkHtml href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</linkHtml>) and <linkHtml href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</linkHtml> (<linkHtml href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</linkHtml>)]</content>. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary <content styleCode="italics">[see <linkHtml href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</linkHtml> (<linkHtml href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</linkHtml>)].</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mild or Moderate CYP3A Inhibitors:</paragraph><list listType="unordered"><item><caption> </caption>Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see <linkHtml href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</linkHtml> (<linkHtml href="#i4i_section_id_30c689c5-c4ac-4245-b169-23d784fda7f3">5.6</linkHtml>, <linkHtml href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</linkHtml>, <linkHtml href="#ID_d05977d5-ff84-489b-bffa-eebc1127623e">5.12</linkHtml>)]</content>.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Monitor tacrolimus whole blood trough concentrations and reduce PROGRAF dose if needed <content styleCode="italics">[see <linkHtml href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</linkHtml> (<linkHtml href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</linkHtml>, <linkHtml href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</linkHtml>) and <linkHtml href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</linkHtml> (<linkHtml href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Other drugs, such as:</paragraph><list listType="unordered"><item><caption> </caption>Magnesium and aluminum hydroxide antacids</item><item><caption> </caption>Metoclopramide</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see <linkHtml href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</linkHtml> (<linkHtml href="#i4i_section_id_30c689c5-c4ac-4245-b169-23d784fda7f3">5.6</linkHtml>, <linkHtml href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</linkHtml>, <linkHtml href="#ID_d05977d5-ff84-489b-bffa-eebc1127623e">5.12</linkHtml>)]</content>.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Monitor tacrolimus whole blood trough concentrations and reduce PROGRAF dose if needed <content styleCode="italics">[see <linkHtml href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</linkHtml> (<linkHtml href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</linkHtml>, <linkHtml href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</linkHtml>) and <linkHtml href="#i4i_clinical_pharmacology_id_
cs">[see <linkHtml href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</linkHtml> (<linkHtml href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</linkHtml>, <linkHtml href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</linkHtml>) and <linkHtml href="#i4i_clinical_pharmacology_id_ 14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</linkHtml> (<linkHtml href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Mild or Moderate CYP3A Inducers</paragraph><list listType="unordered"><item><caption> </caption>Methylprednisolone, prednisone</item></list></td><td styleCode="Rrule Lrule " valign="top"><paragraph>May decrease tacrolimus whole blood trough concentrations.</paragraph></td><td styleCode="Rrule Lrule " valign="top"><paragraph>Monitor tacrolimus whole blood trough concentrations and adjust PROGRAF dose if needed <content styleCode="italics">[see <linkHtml href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</linkHtml> (<linkHtml href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</linkHtml>, <linkHtml href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Caspofungin</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>May decrease tacrolimus whole blood trough concentrations.</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Monitor tacrolimus whole blood trough concentrations and adjust PROGRAF dose if needed <content styleCode="italics">[see <linkHtml href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</linkHtml> (<linkHtml href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</linkHtml>, <linkHtml href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</linkHtml>)]</content>.</paragraph></td></tr></tbody></table>
8 USE IN SPECIFIC POPULATIONS Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. ( 8.1 , 8.3 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to PROGRAF 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data]. The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death. Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported. Maternal Adverse Reactions PROGRAF may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes).
ansplant 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 PROGRAF may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions ( 5.4 )]. PROGRAF may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions ( 5.7 , 5.8 )]. 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 PROGRAF. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to PROGRAF. 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 16 . 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 renal 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 16. 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 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), 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 to 6.9 times the recommended clinical dose range) 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.
o 6.9 times the recommended clinical dose range) 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 to 6.9 times the recommended clinical dose range); 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 to 2.2 times the recommended clinical dose range). 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 to 6.9 times the 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 to 2.2 times the recommended clinical dose range) [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 Use in Specific Populations ( 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 PROGRAF and any potential adverse effects on the breastfed child from PROGRAF or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception PROGRAF 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 PROGRAF [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 PROGRAF [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use Safety and effectiveness have been established in pediatric liver, kidney, heart, and lung transplant patients. Liver Transplantation Safety and efficacy using PROGRAF Granules in pediatric de novo liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received PROGRAF, and supported by two pharmacokinetic and safety studies in 151 children who received PROGRAF. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations. Pediatric patients generally required higher doses of PROGRAF to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )].
clinical status and whole blood concentrations. Pediatric patients generally required higher doses of PROGRAF to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )]. Kidney and Heart Transplantation Use of PROGRAF capsules and PROGRAF Granules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )]. Lung Transplantation The use of PROGRAF capsules and PROGRAF Granules in pediatric lung transplantation is supported by the experience in the U.S. Scientific Registry of Transplant Recipients (SRTR) including 450 pediatric patients receiving tacrolimus immediate-release products in combination with mycophenolate mofetil and 72 pediatric patients receiving tacrolimus immediate-release products in combination with azathioprine between 1999-2017 . 8.5 Geriatric Use Clinical trials of PROGRAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 PROGRAF in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing PROGRAF at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration ( 2.4 ) 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 volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology ( 12.3 )] . The use of PROGRAF in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )]. 8.8 Race or Ethnicity African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]. 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 ( 5.4 )].
<table ID="_Ref514920040" width="100%"><caption>Table 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus</caption><col width="40%"/><col width="29%"/><col width="30%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="middle"/><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Kidney</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Liver</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Pregnancy Outcomes</content><footnote ID="_Ref488226925">Includes multiple births and terminations.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">462</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">253</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">Miscarriage</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24.5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">Live births</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">331</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">180</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pre-term delivery (< 37 weeks)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>49%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Low birth weight (< 2500 g)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Birth defects</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>8%<footnote ID="_Ref54344619">Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>5%</paragraph></td></tr></tbody></table>
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to PROGRAF 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data]. The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death. Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported. Maternal Adverse Reactions PROGRAF may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions ( 5.4 )]. PROGRAF may exacerbate hypertension in pregnant women and increase pre-eclampsia.
fspring were reported. Maternal Adverse Reactions PROGRAF may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions ( 5.4 )]. PROGRAF may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions ( 5.7 , 5.8 )]. 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 PROGRAF. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to PROGRAF. 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 16 . 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 renal 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 16. 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 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), 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 to 6.9 times the recommended clinical dose range) 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.
o 6.9 times the recommended clinical dose range) 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 to 6.9 times the recommended clinical dose range); 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 to 2.2 times the recommended clinical dose range). 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 to 6.9 times the 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 to 2.2 times the recommended clinical dose range) [see Nonclinical Toxicology ( 13.1 )].
8.4 Pediatric Use Safety and effectiveness have been established in pediatric liver, kidney, heart, and lung transplant patients. Liver Transplantation Safety and efficacy using PROGRAF Granules in pediatric de novo liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received PROGRAF, and supported by two pharmacokinetic and safety studies in 151 children who received PROGRAF. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations. Pediatric patients generally required higher doses of PROGRAF to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )]. Kidney and Heart Transplantation Use of PROGRAF capsules and PROGRAF Granules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )]. Lung Transplantation The use of PROGRAF capsules and PROGRAF Granules in pediatric lung transplantation is supported by the experience in the U.S. Scientific Registry of Transplant Recipients (SRTR) including 450 pediatric patients receiving tacrolimus immediate-release products in combination with mycophenolate mofetil and 72 pediatric patients receiving tacrolimus immediate-release products in combination with azathioprine between 1999-2017 .
8.5 Geriatric Use Clinical trials of PROGRAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.
10 OVERDOSAGE Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of PROGRAF [see Adverse Reactions ( 6.1 , 6.2 )] , including tremors, abnormal renal function, hypertension, and peripheral edema; in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
11 DESCRIPTION Tacrolimus, previously known as FK506, is the active ingredient in PROGRAF. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis . Chemically, tacrolimus is designated as [3 S -[3 R *[ E (1 S *,3 S *,4 S *)], 4 S *,5 R *,8 S *,9 E ,12 R *,14 R *,15 S *,16 R *,18 S *,19 S *,26a R *]] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1- c ][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate. The chemical structure of tacrolimus is: Tacrolimus has an empirical formula of C 44 H 69 NO 12 •H 2 O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform. PROGRAF is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, and magnesium stearate NF. The 0.5 mg capsule shell contains ferric oxide NF, gelatin NF and titanium dioxide USP, the 1 mg capsule shell contains gelatin NF and titanium dioxide USP, and the 5 mg capsule shell contains ferric oxide NF, gelatin NF, and titanium dioxide USP. PROGRAF is also available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg anhydrous tacrolimus USP in 1 mL for administration by intravenous infusion only. Each mL contains the following inactive ingredients: dehydrated alcohol USP, 80.0% v/v and polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg. PROGRAF injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use. PROGRAF Granules is available for oral administration as a suspension containing the equivalent of 0.2 mg or 1 mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, and lactose monohydrate NF. Tacrolimus structural formula
12 CLINICAL PHARMACOLOGY 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, 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 Population N Route (Dose) Parameters C max (ng/mL) T max (hr) AUC (ng•hr/mL) t 1/2 (hr) CL (L/hr/kg) V (L/kg) Healthy Volunteers 8 IV (0.025 mg/kg/4 hr) Not applicable 652 AUC 0-inf ± 156 34.2 ± 7.7 0.040 ± 0.009 1.91 ± 0.31 30 PO (5 mg) (granules) 35.6 ± 10.9 1.3 ± 0.5 320 ± 164 32.1 ± 5.9 Not available 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 3.0 203 ± 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 ± 30.0 2.3 ± 1.5 519 ± 179 Heart Transplant Patients 11 IV (0.01 mg/kg/day as a continuous infusion) 954 AUC 0-t ± 334 23.6 ± 9.22 0.051 ± 0.015 11 PO (0.075 mg/kg/day) Determined after the first dose 14.7 ± 7.79 2.1 [0.5-6.0] Median [range] 82.7 AUC 0-12 ± 63.2 14 PO (0.15 mg/kg/day) 24.5 ± 13.7 1.5 [0.4-4.0] 142 ± 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.
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 (C max ) 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 10-12 hours post-dose (C min ) 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. In a healthy volunteer adult study, the systemic exposure to tacrolimus (AUC) for PROGRAF Granules was approximately 16% higher than that for PROGRAF capsules when administered as single doses. 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 C max were decreased 37% and 77%, respectively; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max 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 C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C max was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. In 11 liver transplant patients, PROGRAF administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 ± 18%) and C max (50 ± 19%), as compared to a fasted state. PROGRAF capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of PROGRAF [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 5‑50 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 .
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 ± 1.0% 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 Pediatric Patients PROGRAF capsules Pharmacokinetics in Pediatric Patients Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C max were 337 ± 167 ng·hr/mL and 48.4 ± 27.9 ng/mL, respectively. The absolute bioavailability was 31 ± 24%. Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2 ± 2.4 years of age. Following IV infusion of a 0.06 mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2 ± 5.0 hours and 0.12 ± 0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and C max were 181 ± 65 ng·hr/mL and 30 ± 11 ng/mL, respectively. The absolute bioavailability was 19 ± 14%. Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration ( 2.3 )]. PROGRAF Granules Pharmacokinetics in Pediatric Patients A multicenter, open-label, single arm, pharmacokinetic study (OPTION, NCT01371331) was conducted using tacrolimus granules for oral suspension in pediatric patients undergoing de novo liver, kidney, or heart transplant. After an initial 24‑hour continuous IV infusion of tacrolimus (0.025 mg/kg/hour) for 12 hours to 4 days, oral PROGRAF Granules were dosed at 0.3 mg/kg/day in divided doses twice daily. Tacrolimus whole blood trough concentrations ranged from 5‑15 ng/mL for the first month post-transplant, and 5-10 ng/mL thereafter. Two pharmacokinetic (PK) profiles, AUC, C max , T max and C trough , were taken after the first oral dose (Day 1) and at steady state (Day 7).
t 0.3 mg/kg/day in divided doses twice daily. Tacrolimus whole blood trough concentrations ranged from 5‑15 ng/mL for the first month post-transplant, and 5-10 ng/mL thereafter. Two pharmacokinetic (PK) profiles, AUC, C max , T max and C trough , were taken after the first oral dose (Day 1) and at steady state (Day 7). Subsequent oral doses of PROGRAF Granules were adjusted based on clinical evidence of efficacy, the whole-blood trough levels, and/or occurrence of adverse events. Of 52 patients enrolled, thirty-eight (38) had an evaluable PK profile. The mean pediatric age was 6.1 years for heart transplant, 1.1 years for liver transplant and 3.6 years for kidney transplant. Summary results of PK parameters are presented in Table 18 . Table 18. Summary of Whole Blood PK Parameters of Tacrolimus after Administration of PROGRAF Granules in Pediatric Patients Population N (age range) Parameters AUC tau [hr*ng/mL] mean ± SD C max [ng/mL] mean ± SD T max [hr] mean ± SD C trough [ng/mL] mean ± SD Heart Transplant Patients 12 (0.58-13 years) Day 1 Day 7 224.13 ± 114.30 165.17 ± 39.12 45.61 ± 19.55 32.69 ± 9.78 2.95 ± 4.33 0.84 ± 0.44 12.60 ± 13.40 7.57 ± 1.80 Liver Transplant Patients 14 (0.33-12 years) Day 1 Day 7 210.56 ± 84.01 195.08 ± 94.63 25.11 ± 10.78 30.52 ± 19.35 2.73 ± 1.84 1.71 ± 1.12 13.41 ± 7.11 9.71 ± 4.03 Kidney Transplant Patients 12 (2.42-11 years) Day 1 Day 7 97.40 ± 36.77 208.32 ± 68.75 18.04 ± 8.10 36.63 ± 13.97 1.78 ± 0.88 1.09 ± 0.61 3.54 ± 1.45 8.92 ± 3.59 Renal and Hepatic Impaired Patients The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19 . Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients Population (No. of Patients) Dose AUC 0-t (ng·hr/mL) t 1/2 (hr) V (L/kg) CI (L/hr/kg) Renal Impairment (n = 12) 0.02 mg/kg/4 hr IV 393 ± 123 (t = 60 hr) 26.3 ± 9.2 1.07 ± 0.20 0.038 ± 0.014 Mild Hepatic Impairment (n = 6) 0.02 mg/kg/4 hr IV 367 ± 107 (t = 72 hr) 60.6 ± 43.8 Range: 27.8 – 141 3.1 ± 1.6 0.042 ± 0.02 7.7 mg PO 488 ± 320 (t = 72 hr) 66.1 ± 44.8 Range: 29.5 – 138 3.7 ± 4.7 Corrected for bioavailability 0.034 ± 0.019 Severe Hepatic Impairment (n = 6, IV) 0.02 mg/kg/4 hr IV (n = 2) 0.01 mg/kg/8 hr IV (n = 4) 762 ± 204 (t = 120 hr) 289 ± 117 (t = 144 hr) 198 ± 158 Range: 81 – 436 3.9 ± 1.0 0.017 ± 0.013 (n = 5, PO) 1 patient did not receive the PO dose 8 mg PO (n = 1) 5 mg PO (n = 4) 4 mg PO (n = 1) 658 (t = 120 hr) 533 ± 156 (t = 144 hr) 119 ± 35 Range: 85 – 178 3.1 ± 3.4 0.016 ± 0.011 Patients with Renal Impairment Tacrolimus pharmacokinetics, following a single IV administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers ( Table 19 ) [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.7 )] .
limus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.7 )] . Patients with Cystic Fibrosis Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration ( 2.2 , 2.3 )] . Racial or Ethnic Groups The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of PROGRAF to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (± SD) tacrolimus C max in African-Americans (23.6 ± 12.1 ng/mL) was significantly lower than in Caucasians (40.2 ± 12.6 ng/mL) and the Latino-Americans (36.2 ± 15.8 ng/mL) (p < 0.01). Mean AUC 0-inf tended to be lower in African-Americans (203 ± 115 ng·hr/mL) than Caucasians (344 ± 186 ng·hr/mL) and Latino-Americans (274 ± 150 ng·hr/mL). The mean (± SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was significantly lower than in Caucasians (19 ± 5.8%, p = 0.011). There was no significant difference in mean terminal T 1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration ( 2.2 )]. Male and Female Patients A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences. 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 PROGRAF 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.
[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 and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus C max relative to tacrolimus administration alone [see Drug Interactions ( 7.2 )] . • Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 ± 5% vs. 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 ± 0.129 L/hr/kg vs. 0.148 ± 0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions ( 7.2 )] . • Voriconazole (see complete prescribing information for VFEND) : Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions ( 7.2 )] . • Posaconazole (see complete prescribing information for Noxafil) : Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) C max and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [ s ee Drug Interactions ( 7.2 )] . • Caspofungin (see complete prescribing information for CANCIDAS) : Caspofungin reduced the blood AUC 0-12 of tacrolimus by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C 12hr ) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions ( 7.2 )] . The mechanism of interaction has not been confirmed.
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, 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 Population N Route (Dose) Parameters C max (ng/mL) T max (hr) AUC (ng•hr/mL) t 1/2 (hr) CL (L/hr/kg) V (L/kg) Healthy Volunteers 8 IV (0.025 mg/kg/4 hr) Not applicable 652 AUC 0-inf ± 156 34.2 ± 7.7 0.040 ± 0.009 1.91 ± 0.31 30 PO (5 mg) (granules) 35.6 ± 10.9 1.3 ± 0.5 320 ± 164 32.1 ± 5.9 Not available 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 3.0 203 ± 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 ± 30.0 2.3 ± 1.5 519 ± 179 Heart Transplant Patients 11 IV (0.01 mg/kg/day as a continuous infusion) 954 AUC 0-t ± 334 23.6 ± 9.22 0.051 ± 0.015 11 PO (0.075 mg/kg/day) Determined after the first dose 14.7 ± 7.79 2.1 [0.5-6.0] Median [range] 82.7 AUC 0-12 ± 63.2 14 PO (0.15 mg/kg/day) 24.5 ± 13.7 1.5 [0.4-4.0] 142 ± 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 (C max ) 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 10-12 hours post-dose (C min ) 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. In a healthy volunteer adult study, the systemic exposure to tacrolimus (AUC) for PROGRAF Granules was approximately 16% higher than that for PROGRAF capsules when administered as single doses. 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.
olimus (AUC) for PROGRAF Granules was approximately 16% higher than that for PROGRAF capsules when administered as single doses. 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 C max were decreased 37% and 77%, respectively; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max 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 C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C max was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. In 11 liver transplant patients, PROGRAF administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 ± 18%) and C max (50 ± 19%), as compared to a fasted state. PROGRAF capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of PROGRAF [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 5‑50 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 ± 1.0% 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%.
nation 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 Pediatric Patients PROGRAF capsules Pharmacokinetics in Pediatric Patients Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C max were 337 ± 167 ng·hr/mL and 48.4 ± 27.9 ng/mL, respectively. The absolute bioavailability was 31 ± 24%. Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2 ± 2.4 years of age. Following IV infusion of a 0.06 mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2 ± 5.0 hours and 0.12 ± 0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and C max were 181 ± 65 ng·hr/mL and 30 ± 11 ng/mL, respectively. The absolute bioavailability was 19 ± 14%. Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration ( 2.3 )]. PROGRAF Granules Pharmacokinetics in Pediatric Patients A multicenter, open-label, single arm, pharmacokinetic study (OPTION, NCT01371331) was conducted using tacrolimus granules for oral suspension in pediatric patients undergoing de novo liver, kidney, or heart transplant. After an initial 24‑hour continuous IV infusion of tacrolimus (0.025 mg/kg/hour) for 12 hours to 4 days, oral PROGRAF Granules were dosed at 0.3 mg/kg/day in divided doses twice daily. Tacrolimus whole blood trough concentrations ranged from 5‑15 ng/mL for the first month post-transplant, and 5-10 ng/mL thereafter. Two pharmacokinetic (PK) profiles, AUC, C max , T max and C trough , were taken after the first oral dose (Day 1) and at steady state (Day 7). Subsequent oral doses of PROGRAF Granules were adjusted based on clinical evidence of efficacy, the whole-blood trough levels, and/or occurrence of adverse events. Of 52 patients enrolled, thirty-eight (38) had an evaluable PK profile. The mean pediatric age was 6.1 years for heart transplant, 1.1 years for liver transplant and 3.6 years for kidney transplant. Summary results of PK parameters are presented in Table 18 . Table 18.
rough levels, and/or occurrence of adverse events. Of 52 patients enrolled, thirty-eight (38) had an evaluable PK profile. The mean pediatric age was 6.1 years for heart transplant, 1.1 years for liver transplant and 3.6 years for kidney transplant. Summary results of PK parameters are presented in Table 18 . Table 18. Summary of Whole Blood PK Parameters of Tacrolimus after Administration of PROGRAF Granules in Pediatric Patients Population N (age range) Parameters AUC tau [hr*ng/mL] mean ± SD C max [ng/mL] mean ± SD T max [hr] mean ± SD C trough [ng/mL] mean ± SD Heart Transplant Patients 12 (0.58-13 years) Day 1 Day 7 224.13 ± 114.30 165.17 ± 39.12 45.61 ± 19.55 32.69 ± 9.78 2.95 ± 4.33 0.84 ± 0.44 12.60 ± 13.40 7.57 ± 1.80 Liver Transplant Patients 14 (0.33-12 years) Day 1 Day 7 210.56 ± 84.01 195.08 ± 94.63 25.11 ± 10.78 30.52 ± 19.35 2.73 ± 1.84 1.71 ± 1.12 13.41 ± 7.11 9.71 ± 4.03 Kidney Transplant Patients 12 (2.42-11 years) Day 1 Day 7 97.40 ± 36.77 208.32 ± 68.75 18.04 ± 8.10 36.63 ± 13.97 1.78 ± 0.88 1.09 ± 0.61 3.54 ± 1.45 8.92 ± 3.59 Renal and Hepatic Impaired Patients The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19 . Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients Population (No. of Patients) Dose AUC 0-t (ng·hr/mL) t 1/2 (hr) V (L/kg) CI (L/hr/kg) Renal Impairment (n = 12) 0.02 mg/kg/4 hr IV 393 ± 123 (t = 60 hr) 26.3 ± 9.2 1.07 ± 0.20 0.038 ± 0.014 Mild Hepatic Impairment (n = 6) 0.02 mg/kg/4 hr IV 367 ± 107 (t = 72 hr) 60.6 ± 43.8 Range: 27.8 – 141 3.1 ± 1.6 0.042 ± 0.02 7.7 mg PO 488 ± 320 (t = 72 hr) 66.1 ± 44.8 Range: 29.5 – 138 3.7 ± 4.7 Corrected for bioavailability 0.034 ± 0.019 Severe Hepatic Impairment (n = 6, IV) 0.02 mg/kg/4 hr IV (n = 2) 0.01 mg/kg/8 hr IV (n = 4) 762 ± 204 (t = 120 hr) 289 ± 117 (t = 144 hr) 198 ± 158 Range: 81 – 436 3.9 ± 1.0 0.017 ± 0.013 (n = 5, PO) 1 patient did not receive the PO dose 8 mg PO (n = 1) 5 mg PO (n = 4) 4 mg PO (n = 1) 658 (t = 120 hr) 533 ± 156 (t = 144 hr) 119 ± 35 Range: 85 – 178 3.1 ± 3.4 0.016 ± 0.011 Patients with Renal Impairment Tacrolimus pharmacokinetics, following a single IV administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers ( Table 19 ) [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.7 )] . Patients with Cystic Fibrosis Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration ( 2.2 , 2.3 )] . Racial or Ethnic Groups The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of PROGRAF to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers.
crolimus has been reported in patients with cystic fibrosis [see Dosage and Administration ( 2.2 , 2.3 )] . Racial or Ethnic Groups The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of PROGRAF to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (± SD) tacrolimus C max in African-Americans (23.6 ± 12.1 ng/mL) was significantly lower than in Caucasians (40.2 ± 12.6 ng/mL) and the Latino-Americans (36.2 ± 15.8 ng/mL) (p < 0.01). Mean AUC 0-inf tended to be lower in African-Americans (203 ± 115 ng·hr/mL) than Caucasians (344 ± 186 ng·hr/mL) and Latino-Americans (274 ± 150 ng·hr/mL). The mean (± SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was significantly lower than in Caucasians (19 ± 5.8%, p = 0.011). There was no significant difference in mean terminal T 1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration ( 2.2 )]. Male and Female Patients A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences. 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 PROGRAF 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 )] .
rease 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 and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus C max relative to tacrolimus administration alone [see Drug Interactions ( 7.2 )] . • Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 ± 5% vs. 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 ± 0.129 L/hr/kg vs. 0.148 ± 0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions ( 7.2 )] . • Voriconazole (see complete prescribing information for VFEND) : Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions ( 7.2 )] . • Posaconazole (see complete prescribing information for Noxafil) : Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) C max and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [ s ee Drug Interactions ( 7.2 )] . • Caspofungin (see complete prescribing information for CANCIDAS) : Caspofungin reduced the blood AUC 0-12 of tacrolimus by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C 12hr ) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions ( 7.2 )] . The mechanism of interaction has not been confirmed.
<table ID="_Ref514841689" cellpadding="5.75pt" width="100%"><caption>Table 17. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients</caption><col width="12%"/><col width="6%"/><col width="22%"/><col width="10%"/><col width="10%"/><col width="12%"/><col width="8%"/><col width="11%"/><col width="8%"/><thead><tr><th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Population</content></th><th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">N</content></th><th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Route</content> <content styleCode="bold">(Dose)</content></th><th align="center" colspan="6" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Parameters</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">C<sub>max</sub></content> <content styleCode="bold">(ng/mL)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">T<sub>max</sub></content> <content styleCode="bold">(hr)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">AUC</content> <content styleCode="bold">(ng•hr/mL)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">t<sub>1/2</sub></content> <content styleCode="bold">(hr)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">CL</content> <content styleCode="bold">(L/hr/kg)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">V</content> <content styleCode="bold">(L/kg)</content></th></tr></thead><tbody><tr><td rowspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Healthy</paragraph><paragraph> Volunteers</paragraph><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>8</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>IV (0.025 mg/kg/4 hr)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><footnote ID="_Ref480453436">Not applicable</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>652<footnote ID="_Ref54341912">AUC<sub>0-inf</sub></footnote> ± 156</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>34.2 ± 7.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0.040 ± 0.009</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1.91 ± 0.31</paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>30</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (5 mg) (granules)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>35.6 ± 10.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.3 ± 0.5</paragraph></td><td
styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (5 mg) (granules)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>35.6 ± 10.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.3 ± 0.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>320<footnoteRef IDREF="_Ref54341912"/> ± 164</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>32.1 ± 5.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnote ID="_Ref480453772">Not available</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (5 mg) (capsules)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>28.8 ± 8.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.5 ± 0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>266<footnoteRef IDREF="_Ref54341912"/> ± 95</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>32.3 ± 8.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr><tr><td rowspan="3" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Kidney</paragraph><paragraph> Transplant</paragraph><paragraph> Patients</paragraph></td><td align="center" rowspan="3" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>26</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>IV (0.02 mg/kg/12 hr)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>294<footnoteRef IDREF="_Ref54341912"/> ± 262</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18.8 ± 16.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.083 ± 0.050</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.41 ± 0.66</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (0.2 mg/kg/day)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>19.2 ± 10.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>3.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>203<footnoteRef IDREF="_Ref54341912"/> ± 42</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (0.3 mg/kg/day)</paragraph></td><td align="center" styleCode
h><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (0.3 mg/kg/day)</paragraph></td><td align="center" styleCode ="Rrule Lrule Botrule " valign="middle"><paragraph>24.2 ± 15.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>288<footnoteRef IDREF="_Ref54341912"/> ± 93</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Liver</paragraph><paragraph> Transplant</paragraph><paragraph> Patients</paragraph></td><td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>17</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>IV (0.05 mg/kg/12 hr)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>3300<footnoteRef IDREF="_Ref54341912"/> ± 2130</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>11.7 ± 3.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.053 ± 0.017</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.85 ± 0.30</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (0.3 mg/kg/day)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>68.5 ± 30.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.3 ± 1.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>519<footnoteRef IDREF="_Ref54341912"/> ± 179</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr><tr><td rowspan="3" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Heart</paragraph><paragraph> Transplant Patients</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>11</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>IV (0.01 mg/kg/day as a continuous infusion)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>954<footnote ID="_Ref480454027">AUC<sub>0-t</sub></footnote> &#x
eRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>954<footnote ID="_Ref480454027">AUC<sub>0-t</sub></footnote> &#x B1; 334</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>23.6 ± 9.22</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.051 ± 0.015</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>11</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (0.075 mg/kg/day)<footnote ID="_Ref480454074">Determined after the first dose</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>14.7 ± 7.79</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.1 [0.5-6.0]<footnote ID="_Ref480454139">Median [range]</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>82.7<footnote ID="_Ref480454167">AUC<sub>0-12</sub></footnote> ± 63.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>14</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>PO (0.15 mg/kg/day)<footnoteRef IDREF="_Ref480454074"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>24.5 ± 13.7</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>1.5 [0.4-4.0]<footnoteRef IDREF="_Ref480454139"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>142<footnoteRef IDREF="_Ref480454167"/> ± 116</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr></tbody></table>
="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr></tbody></table> <table ID="_Ref514842488" width="100%"><caption>Table 18.
="_Ref480453436"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><footnoteRef IDREF="_Ref480453772"/></paragraph></td></tr></tbody></table> <table ID="_Ref514842488" width="100%"><caption>Table 18. Summary of Whole Blood PK Parameters of Tacrolimus after Administration of PROGRAF Granules in Pediatric Patients</caption><col width="12%"/><col width="16%"/><col width="8%"/><col width="16%"/><col width="16%"/><col width="16%"/><col width="16%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Population</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">N</content></paragraph><paragraph><content styleCode="bold">(age range)</content></paragraph></td><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Parameters</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">AUC<sub>tau</sub> [hr*ng/mL]</content></paragraph><paragraph>mean ± SD</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">C<sub>max</sub> [ng/mL]</content></paragraph><paragraph>mean ± SD</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">T<sub>max</sub> [hr]</content></paragraph><paragraph>mean ± SD</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">C<sub>trough</sub> [ng/mL]</content></paragraph><paragraph>mean ± SD</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Heart Transplant Patients</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>12 </paragraph><paragraph>(0.58-13 years)</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Day 1</paragraph><paragraph>Day 7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>224.13 ± 114.30</paragraph><paragraph>165.17 ± 39.12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>45.61 ± 19.55</paragraph><paragraph>32.69 ± 9.78</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.95 ± 4.33</paragraph><paragraph>0.84 ± 0.44</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>12.60 ± 13.40</paragraph><paragraph>7.57 ± 1.80</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Liver Transplant Patients</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>14 </paragraph><paragraph>(0.33-12 years)</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Day 1</paragraph><paragraph>Day 7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>210.56 ± 84.01</paragraph><paragraph>195.08 ± 94.63</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>25.11 ± 10.78</paragraph><paragraph>30.52 ± 19.35</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.73 ± 1.84</paragraph><paragraph>1.71 ± 1.12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrul
e Lrule Botrule " valign="middle"><paragraph>25.11 ± 10.78</paragraph><paragraph>30.52 ± 19.35</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.73 ± 1.84</paragraph><paragraph>1.71 ± 1.12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrul e " valign="middle"><paragraph>13.41 ± 7.11</paragraph><paragraph>9.71 ± 4.03</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Kidney Transplant Patients</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>12 </paragraph><paragraph>(2.42-11 years)</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Day 1</paragraph><paragraph>Day 7</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>97.40 ± 36.77</paragraph><paragraph>208.32 ± 68.75</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>18.04 ± 8.10</paragraph><paragraph>36.63 ± 13.97</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>1.78 ± 0.88</paragraph><paragraph>1.09 ± 0.61</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>3.54 ± 1.45</paragraph><paragraph>8.92 ± 3.59</paragraph></td></tr></tbody></table> <table ID="_Ref514842938" width="100%"><caption>Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients</caption><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Population</content></paragraph><paragraph><content styleCode="bold">(No.
Impaired Adult Patients</caption><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Population</content></paragraph><paragraph><content styleCode="bold">(No. of Patients)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Dose</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">AUC<sub>0-t</sub></content></paragraph><paragraph><content styleCode="bold">(ng·hr/mL)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">t<sub>1/2</sub></content></paragraph><paragraph><content styleCode="bold">(hr)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">V</content></paragraph><paragraph><content styleCode="bold">(L/kg)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">CI</content></paragraph><paragraph><content styleCode="bold">(L/hr/kg)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Renal</paragraph><paragraph> Impairment</paragraph><paragraph> (n = 12)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.02</paragraph><paragraph>mg/kg/4 hr</paragraph><paragraph>IV</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>393 ± 123</paragraph><paragraph>(t = 60 hr)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26.3 ± 9.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.07 ± 0.20</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.038 ± 0.014</paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Mild Hepatic </paragraph><paragraph> Impairment</paragraph><paragraph> (n = 6)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.02</paragraph><paragraph>mg/kg/4 hr</paragraph><paragraph>IV</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>367 ± 107</paragraph><paragraph>(t = 72 hr)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>60.6 ± 43.8</paragraph><paragraph>Range: 27.8 – 141</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.1 ± 1.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.042 ± 0.02</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.7 mg</paragraph><paragraph>PO</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>488 ± 320</paragraph><paragraph>(t = 72 hr)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>66.1 ± 44.8</paragraph><paragraph>Range: 29.5 – 138</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.7 ± 4.7<footnote ID="_Refid-25151c80-c99a-415b-8ad5-c257fb778">Corrected for bioavailability</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.034 ± 0.019<footnoteRef IDREF="_Refid-25151c80-c99a-415b-8ad5-c257fb778"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Severe</paragraph><paragraph> Hepatic</paragraph><paragraph> Imp
aragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.034 ± 0.019<footnoteRef IDREF="_Refid-25151c80-c99a-415b-8ad5-c257fb778"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Severe</paragraph><paragraph> Hepatic</paragraph><paragraph> Imp airment</paragraph><paragraph> (n = 6, IV)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.02 mg/kg/4 hr</paragraph><paragraph>IV (n = 2) 0.01 mg/kg/8 hr</paragraph><paragraph>IV (n = 4)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>762 ± 204</paragraph><paragraph>(t = 120 hr) 289 ± 117</paragraph><paragraph>(t = 144 hr)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>198 ± 158</paragraph><paragraph>Range: 81 – 436</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.9 ± 1.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.017 ± 0.013</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> (n = 5, PO)<footnote ID="_Ref54344708">1 patient did not receive the PO dose</footnote></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8 mg PO</paragraph><paragraph>(n = 1) 5 mg PO</paragraph><paragraph>(n = 4)</paragraph><paragraph>4 mg PO</paragraph><paragraph>(n = 1)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>658</paragraph><paragraph>(t = 120 hr) 533 ± 156</paragraph><paragraph>(t = 144 hr)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>119 ± 35</paragraph><paragraph>Range: 85 – 178</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.1 ± 3.4<footnoteRef IDREF="_Refid-25151c80-c99a-415b-8ad5-c257fb778"/></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.016 ± 0.011<footnoteRef IDREF="_Refid-25151c80-c99a-415b-8ad5-c257fb778"/></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr></tbody></table>
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions ( 5.1 )] . A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m 2 /day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown. The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis. Mutagenesis No evidence of genotoxicity was seen in bacterial ( Salmonella and E. coli ) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Impairment of Fertility Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m 2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions ( 5.1 )] . A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m 2 /day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown. The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis. Mutagenesis No evidence of genotoxicity was seen in bacterial ( Salmonella and E. coli ) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Impairment of Fertility Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m 2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
14 CLINICAL STUDIES 14.1 Kidney Transplantation PROGRAF/Azathioprine (AZA) PROGRAF-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded. There were 205 patients randomized to PROGRAF-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids, and azathioprine. Overall, 1-year patient and graft survivals were 96.1% and 89.6%, respectively. Data from this trial of PROGRAF in conjunction with azathioprine indicate that during the first 3 months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year. PROGRAF/Mycophenolate Mofetil (MMF) PROGRAF-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multicenter trial (Study 1), 1589 kidney transplant patients received PROGRAF (Group C, n = 401), sirolimus (Group D, n = 399), or one of two cyclosporine (CsA) regimens (Group A, n = 390 and Group B, n = 399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving PROGRAF/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the PROGRAF group exhibited higher estimated creatinine clearance rates (eCL cr ) using the Cockcroft-Gault formula ( Table 20 ) and experienced fewer efficacy failures, defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or loss to follow-up ( Table 21 ) in comparison to each of the other three groups. Patients randomized to PROGRAF/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions ( 6.1 )]. Table 20. Estimated Creatinine Clearance at 12 Months (Study 1) Group eCL cr [mL/min] at Month 12 All death/graft loss (n = 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n = 10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. N MEAN SD MEDIAN Treatment Difference with Group C (99.2% CI Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
ubjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. N MEAN SD MEDIAN Treatment Difference with Group C (99.2% CI Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. ) (A) CsA/MMF/CS 390 56.5 25.8 56.9 -8.6 (-13.7, -3.7) (B) CsA/MMF/CS/Daclizumab 399 58.9 25.6 60.9 -6.2 (-11.2, -1.2) (C) Tac/MMF/CS/Daclizumab 401 65.1 27.4 66.2 - (D) Siro/MMF/CS/Daclizumab 399 56.2 27.4 57.3 -8.9 (-14.1, -3.9) Total 1589 59.2 26.8 60.5 Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus Table 21. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1) Group A N = 390 Group B N = 399 Group C N = 401 Group D N = 399 Overall Failure 141 (36.2%) 126 (31.6%) 82 (20.4%) 185 (46.4%) Components of efficacy failure BPAR 113 (29.0%) 106 (26.6%) 60 (15.0%) 152 (38.1%) Graft loss excluding death 28 (7.2%) 20 (5.0%) 12 (3.0%) 30 (7.5%) Mortality 13 (3.3%) 7 (1.8%) 11 (2.7%) 12 (3.0%) Lost to follow-up 5 (1.3%) 7 (1.8%) 5 (1.3%) 6 (1.5%) Treatment Difference of efficacy failure compared to Group C (99.2% CI Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. ) 15.8% (7.1%, 24.3%) 11.2% (2.7%, 19.5%) - 26.0% (17.2%, 34.7%) Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab The protocol-specified target tacrolimus trough concentrations (C trough , Tac ) were 3-7 ng/mL; however, the observed median C troughs , Tac approximated 7 ng/mL throughout the 12-month trial ( Table 22 ). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant. Table 22. Tacrolimus Whole Blood Trough Concentration Range (Study 1) Time Median (P10-P90 10 to 90 th Percentile: range of C trough , Tac that excludes lowest 10% and highest 10% of C trough , Tac ) tacrolimus whole blood trough concentration range (ng/mL) Day 30 (N = 366) 6.9 (4.4 – 11.3) Day 90 (N = 351) 6.8 (4.1 – 10.7) Day 180 (N = 355) 6.5 (4.0 – 9.6) Day 365 (N = 346) 6.5 (3.8 – 10.0) The protocol-specified target cyclosporine trough concentrations (C trough , CsA ) for Group B were 50-100 ng/mL; however, the observed median C troughs , CsA approximated 100 ng/mL throughout the 12-month trial. The protocol-specified target C troughs , CsA for Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median C troughs , CsA approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12. While patients in all groups started MMF at 1 gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 ( Table 23 ); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions. Table 23. MMF Dose Over Time in PROGRAF/MMF (Group C) (Study 1) Time period (Days) Time-averaged MMF dose (grams per day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.
RAF/MMF (Group C) (Study 1) Time period (Days) Time-averaged MMF dose (grams per day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. Less than 2.0 2.0 Greater than 2.0 0-30 (N = 364) 37% 60% 2% 0-90 (N = 373) 47% 51% 2% 0-180 (N = 377) 56% 42% 2% 0-365 (N = 380) 63% 36% 1% Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) In a second randomized, open-label, multicenter trial (Study 2), 424 kidney transplant patients received PROGRAF (N = 212) or cyclosporine (N = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the PROGRAF/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving PROGRAF/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to over-immunosuppression ( Table 24 ). Table 24. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2) PROGRAF/MMF Cyclosporine/MMF (N = 212) (N = 212) Overall Failure 32 (15.1%) 36 (17.0%) Components of efficacy failure BPAR 16 (7.5%) 29 (13.7%) Graft loss excluding death 6 (2.8%) 4 (1.9%) Mortality 9 (4.2%) 5 (2.4%) Lost to follow-up 4 (1.9%) 1 (0.5%) Treatment Difference of efficacy failure compared to PROGRAF/MMF group (95% CI 95% confidence interval calculated using Fisher's Exact Test. ) 1.9% (-5.2%, 9.0%) The protocol-specified target tacrolimus whole blood trough concentrations (C trough , Tac ) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median C troughs , Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 ( Table 25 ). Approximately 80% of patients maintained tacrolimus whole blood trough concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year. Table 25. Tacrolimus Whole Blood Trough Concentration Range (Study 2) Time Median (P10-P90 10 to 90 th Percentile: range of C trough , Tac that excludes lowest 10% and highest 10% of C trough , Tac. ) tacrolimus whole blood trough concentration range (ng/mL) Day 30 (N = 174) 10.5 (6.3 – 16.8) Day 60 (N = 179) 9.2 (5.9 – 15.3) Day 120 (N = 176) 8.3 (4.6 – 13.3) Day 180 (N = 171) 7.8 (5.5 – 13.2) Day 365 (N = 178) 7.1 (4.2 – 12.4) The protocol-specified target cyclosporine whole blood concentrations (C trough , CsA ) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median C troughs , CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12. Patients in both groups started MMF at 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the PROGRAF/MMF group ( Table 26 ) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the PROGRAF/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions ( 6.1 )] . Table 26. MMF Dose Over Time in the PROGRAF/MMF Group (Study 2) Time period (Days) Time-averaged MMF dose (g/day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods.
ver Time in the PROGRAF/MMF Group (Study 2) Time period (Days) Time-averaged MMF dose (g/day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods. Less than 2.0 2.0 Greater than 2.0 0-30 (N = 212) 25% 69% 6% 0-90 (N = 212) 41% 53% 6% 0-180 (N = 212) 52% 41% 7% 0-365 (N = 212) 62% 34% 4% Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) 14.2 Liver Transplantation The safety and efficacy of PROGRAF-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation. In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the PROGRAF-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed. In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the PROGRAF-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases. One-year patient survival and graft survival in the PROGRAF-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and PROGRAF-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and PROGRAF-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral PROGRAF dosing was 2 days. Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients are often maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL. Pediatric Liver Transplantation Using PROGRAF Granules The efficacy and safety of PROGRAF Granules plus corticosteroids were compared with a triple regimen of cyclosporine/corticosteroids/azathioprine in a randomized, open-label study, in de novo pediatric liver transplant patients. The study was conducted outside the United States and enrolled patients aged 16 years or younger. The distribution of pediatric patients by age was similar in both treatment groups, with a majority < 5 years.
corticosteroids/azathioprine in a randomized, open-label study, in de novo pediatric liver transplant patients. The study was conducted outside the United States and enrolled patients aged 16 years or younger. The distribution of pediatric patients by age was similar in both treatment groups, with a majority < 5 years. Patients were randomized to either tacrolimus for oral suspension 0.3 mg/kg/day (N = 91) or cyclosporine 10 mg/kg/day orally (N = 90) initiated 6 hours after completion of transplant surgery. Doses throughout the 1-year study period were adjusted to maintain whole blood trough levels within 5-20 ng/mL [see Dosage and Administration ( 2.3 )]. Based on trough levels, doses of tacrolimus were adjusted to 0.17 mg/kg/day and 0.14 mg/kg/day by days 2 and 3, respectively. At 12 months, the incidence rate of BPAR, graft loss, death, or loss to follow-up was 52.7% in the tacrolimus group and 61.1% in the cyclosporine group ( Table 27 ). Table 27. Key Efficacy Results at 12 Months in Pediatric Liver Transplant Recipients Receiving PROGRAF Granules or Cyclosporine PROGRAF Granules (N = 91) Cyclosporine (N = 90) Overall Failure 48 (52.7%) 55 (61.1%) Components of efficacy failure BPAR 40 (44.0%) 49 (54.4%) Graft loss 7 (7.7%) 13 (14.4%) Graft loss excluding death 1 (1.1%) 6 (6.7%) Mortality 6 (6.6%) 7 (7.8%) Lost to follow-up 2 (2.2%) 0 Treatment Difference of efficacy failure compared to cyclosporine (95% CI 95% confidence interval calculated using normal approximation. ) -8.4% (-22.7%, 6.0%) 14.3 Heart Transplantation Two open-label, randomized, comparative trials evaluated the safety and efficacy of PROGRAF-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with PROGRAF or cyclosporine modified for 18 months. In a 3-arm trial conducted in the U.S., 331 patients received corticosteroids and PROGRAF plus sirolimus, PROGRAF plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year. In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the PROGRAF plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from 1 week to 3 months post-transplant, approximately 80% of patients maintained trough concentrations between 8 to 20 ng/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to 18 ng/mL. The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose PROGRAF; however, this regimen was associated with increased risk of wound-healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions ( 5.10 )]. 14.4 Lung Transplantation The efficacy and safety of PROGRAF-based immunosuppression in primary lung transplantation were assessed in a non-interventional (observational) study using data from the U.S. Scientific Registry of Transplant Recipients (SRTR).
, and is not recommended [see Warnings and Precautions ( 5.10 )]. 14.4 Lung Transplantation The efficacy and safety of PROGRAF-based immunosuppression in primary lung transplantation were assessed in a non-interventional (observational) study using data from the U.S. Scientific Registry of Transplant Recipients (SRTR). The study analyzed outcomes based on discharge immunosuppression treatment regimen in recipients of a primary lung transplant between 1999 and 2017 who were alive at the time of discharge. In adult patients receiving tacrolimus immediate-release products in combination with MMF (n=15,478) or tacrolimus immediate-release products in combination with AZA (n=4,263), the one-year graft survival estimates from time of discharge were 90.9% and 90.8%, respectively. In pediatric patients receiving tacrolimus immediate-release products in combination with MMF (n= 450) or tacrolimus immediate-release products in combination with AZA (n=72), the one-year graft survival estimates from time of discharge were 91.7% and 84.7%, respectively.
<table ID="_Ref514843310" width="100%"><caption>Table 20. Estimated Creatinine Clearance at 12 Months (Study 1)</caption><col width="34%"/><col width="11%"/><col width="11%"/><col width="11%"/><col width="11%"/><col width="21%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Group</content></th><th align="center" colspan="5" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">eCL<sub>cr</sub> [mL/min] at Month 12</content><footnote ID="_Refid-5b0e175b-fe09-49ef-a696-b3223cb86">All death/graft loss (n = 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n = 10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing.
erular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. </footnote></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">MEAN</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">SD</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">MEDIAN</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">Treatment Difference with Group C (99.2% CI</content><footnote ID="_Ref514843380">Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.</footnote><content styleCode="bold">)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> (A) CsA/MMF/CS </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>390</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>56.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>25.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>56.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-8.6 (-13.7, -3.7)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> (B) CsA/MMF/CS/Daclizumab</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>399</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>58.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>25.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>60.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-6.2 (-11.2, -1.2)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> (C) Tac/MMF/CS/Daclizumab </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>401</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>65.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>66.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> (D) Siro/MMF/CS/Daclizumab </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>399</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>56.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>57.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-8.9 (-14.1, -3.9)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Total</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1589</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>59.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><para
" styleCode="Rrule Botrule " valign="top"><paragraph>1589</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>59.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><para graph>60.5</paragraph></td><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td colspan="6" styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus</paragraph></td></tr></tbody></table> <table ID="_Ref514843603" width="100%"><caption>Table 21.
graph>60.5</paragraph></td><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td colspan="6" styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus</paragraph></td></tr></tbody></table> <table ID="_Ref514843603" width="100%"><caption>Table 21. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1)</caption><col width="29%"/><col width="16%"/><col width="19%"/><col width="16%"/><col width="19%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Group A</content> <content styleCode="bold">N = 390</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Group B</content> <content styleCode="bold">N = 399</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Group C</content> <content styleCode="bold">N = 401</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Group D</content> <content styleCode="bold">N = 399</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Overall Failure</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>141 (36.2%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>126 (31.6%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>82 (20.4%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>185 (46.4%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Components of efficacy failure</paragraph></td><td styleCode="Rrule Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> BPAR</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>113 (29.0%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>106 (26.6%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>60 (15.0%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>152 (38.1%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Graft loss excluding death</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>28 (7.2%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>20 (5.0%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12 (3.0%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>30 (7.5%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Mortality</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>13 (3.3%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7 (1.8%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11 (2.7%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12 (3.0%) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lost to follow-up</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5 (1.3%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7 (1.8%)</paragraph></td><td align="center" styleCode="Rrule
d styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lost to follow-up</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5 (1.3%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7 (1.8%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5 (1.3%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6 (1.5%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Treatment Difference of efficacy failure compared to Group C (99.2% CI<footnote ID="_Refid-2d090406-ca85-4829-85a3-316b12717">Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.</footnote>)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>15.8%</paragraph><paragraph>(7.1%, 24.3%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>11.2%</paragraph><paragraph>(2.7%, 19.5%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>-</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>26.0%</paragraph><paragraph>(17.2%, 34.7%)</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab</paragraph></td></tr></tbody></table>
" valign="middle"><paragraph>26.0%</paragraph><paragraph>(17.2%, 34.7%)</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab</paragraph></td></tr></tbody></table> <table ID="_Ref514843647" width="100%"><caption>Table 22. Tacrolimus Whole Blood Trough Concentration Range (Study 1)</caption><col width="25%"/><col width="75%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Time </content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Median (P10-P90</content><footnote ID="_Refid-7a8a0ae8-54bd-40df-b0ad-ff510b055">10 to 90<sup>th</sup> Percentile: range of C<sub>trough</sub>,<sub>Tac </sub>that excludes lowest 10% and highest 10% of C<sub>trough</sub>,<sub>Tac</sub></footnote><content styleCode="bold">) tacrolimus whole blood trough concentration range</content> <content styleCode="bold">(ng/mL)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Day 30 (N = 366)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.9 (4.4 – 11.3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Day 90 (N = 351)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.8 (4.1 – 10.7)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Day 180 (N = 355)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.5 (4.0 – 9.6)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Day 365 (N = 346)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.5 (3.8 – 10.0)</paragraph></td></tr></tbody></table>
ode="Rrule Botrule " valign="top"><paragraph>6.5 (4.0 – 9.6)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Day 365 (N = 346)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.5 (3.8 – 10.0)</paragraph></td></tr></tbody></table> <table ID="_Ref514843732" width="100%"><caption>Table 23. MMF Dose Over Time in PROGRAF/MMF (Group C) (Study 1)</caption><col width="22%"/><col width="24%"/><col width="27%"/><col width="27%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Time period (Days)</content></th><th align="center" colspan="3" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Time-averaged MMF dose (grams per day)</content><footnote ID="_Refid-1fdc24d2-378e-4de6-99d9-6fb80c439">Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. </footnote></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top">Less than 2.0</th><th align="center" styleCode="Rrule Botrule " valign="top">2.0</th><th align="center" styleCode="Rrule Botrule " valign="top">Greater than 2.0</th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0-30 (N = 364)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>60%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0-90 (N = 373)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>51%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0-180 (N = 377)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>42%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0-365 (N = 380)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>63%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</paragraph></td></tr></tbody></table>
gn="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</paragraph></td></tr></tbody></table> <table ID="_Ref514843793" width="100%"><caption>Table 24. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2)</caption><col width="39%"/><col width="30%"/><col width="31%"/><thead><tr><th align="left" styleCode="Rrule Lrule Toprule " valign="top"> </th><th align="center" styleCode="Rrule Toprule " valign="top"><content styleCode="bold">PROGRAF/MMF</content></th><th align="center" styleCode="Rrule Toprule " valign="top"><content styleCode="bold">Cyclosporine/MMF</content></th></tr><tr><th align="left" styleCode="Rrule Lrule Botrule " valign="top"> </th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">(N = 212)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">(N = 212)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Overall Failure</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32 (15.1%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36 (17.0%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Components of efficacy failure</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> BPAR</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16 (7.5%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29 (13.7%) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Graft loss excluding death</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (2.8%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (1.9%) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Mortality</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (4.2%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (2.4%) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lost to follow-up</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (1.9%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Treatment Difference of efficacy failure compared to PROGRAF/MMF group (95% CI<footnote ID="_Refid-9ab839c4-896e-4a16-99da-12b7fce4f">95% confidence interval calculated using Fisher's Exact Test.</footnote>)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>1.9% (-5.2%, 9.0%)</paragraph></td></tr></tbody></table>
confidence interval calculated using Fisher's Exact Test.</footnote>)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>1.9% (-5.2%, 9.0%)</paragraph></td></tr></tbody></table> <table ID="_Ref514843846" width="100%"><caption>Table 25. Tacrolimus Whole Blood Trough Concentration Range (Study 2)</caption><col width="30%"/><col width="70%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Time </content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Median (P10-P90</content><footnote ID="_Refid-21e5bd56-9466-4d71-a1ac-17bc68ef9">10 to 90<sup>th</sup> Percentile: range of C<sub>trough</sub>,<sub>Tac</sub> that excludes lowest 10% and highest 10% of C<sub>trough</sub>,<sub>Tac.</sub></footnote><content styleCode="bold">) tacrolimus whole blood trough concentration range</content> <content styleCode="bold">(ng/mL)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Day 30 (N = 174)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10.5 (6.3 – 16.8)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Day 60 (N = 179)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9.2 (5.9 – 15.3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Day 120 (N = 176)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.3 (4.6 – 13.3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Day 180 (N = 171)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7.8 (5.5 – 13.2)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Day 365 (N = 178)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7.1 (4.2 – 12.4)</paragraph></td></tr></tbody></table>
de="Rrule Botrule " valign="top"><paragraph>7.8 (5.5 – 13.2)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Day 365 (N = 178)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7.1 (4.2 – 12.4)</paragraph></td></tr></tbody></table> <table ID="_Ref514846713" width="100%"><caption>Table 26. MMF Dose Over Time in the PROGRAF/MMF Group (Study 2)</caption><col width="24%"/><col width="24%"/><col width="26%"/><col width="26%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Time period (Days)</content></th><th align="center" colspan="3" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Time-averaged MMF dose (g/day)</content><footnote ID="_Refid-fa85cced-5c3b-48ff-a921-75e8e135f">Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods. </footnote></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top">Less than 2.0</th><th align="center" styleCode="Rrule Botrule " valign="top">2.0</th><th align="center" styleCode="Rrule Botrule " valign="top">Greater than 2.0</th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0-30 (N = 212)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>69%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0-90 (N = 212)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>41%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>53%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0-180 (N = 212)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>52%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>41%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 0-365 (N = 212)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>62%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</paragraph></td></tr></tbody></table>
ign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</paragraph></td></tr></tbody></table> <table ID="_Ref514846756" cellpadding="0pt" width="99.04%"><caption>Table 27. Key Efficacy Results at 12 Months in Pediatric Liver Transplant Recipients Receiving PROGRAF Granules or Cyclosporine</caption><col width="50%"/><col width="26%"/><col width="24%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">PROGRAF Granules</content> <content styleCode="bold">(N = 91)</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Cyclosporine</content> <content styleCode="bold">(N = 90)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Overall Failure</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48 (52.7%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>55 (61.1%)</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Components of efficacy failure</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> BPAR</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40 (44.0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>49 (54.4%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Graft loss</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (7.7%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13 (14.4%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Graft loss excluding death</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1.1%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (6.7%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Mortality</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (6.6%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (7.8%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lost to follow-up</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2.2%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Treatment Difference of efficacy failure compared to cyclosporine (95% CI<footnote ID="_Ref514846843">95% confidence interval calculated using normal approximation.</footnote>)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>-8.4% (-22.7%, 6.0%)</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"/></tr></tbody></table>
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 PROGRAF (tacrolimus) Capsules, USP Strength 0.5 mg (containing the equivalent of 0.5 mg anhydrous tacrolimus USP) 1 mg (containing the equivalent of 1 mg anhydrous tacrolimus USP) 5 mg (containing the equivalent of 5 mg anhydrous tacrolimus USP) Shape/color oblong/light yellow oblong/white oblong/grayish red Branding on capsule cap/body 607 617 657 100 count bottle NDC 0469-0607-73 NDC 0469-0617-73 NDC 0469-0657-73 Note: PROGRAF capsules USP are not filled to maximum capsule capacity. Capsule contains labeled amount. Store and Dispense Store at 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. f f f 16.2 PROGRAF (tacrolimus) Injection (for Intravenous infusion only) NDC 0469-3016-01 Product Code 301601 5 mg/mL (equivalent of 5 mg of anhydrous tacrolimus USP per mL) supplied as a sterile solution in a 1 mL ampule, in boxes of 10 ampules Store and Dispense Store between 5°C and 25°C (41°F and 77°F). 16.3 PROGRAF Granules (tacrolimus for oral suspension) Strength 0.2 mg (containing the equivalent of 0.2 mg anhydrous tacrolimus USP) 1 mg (containing the equivalent of 1 mg anhydrous tacrolimus USP) Shape/color White granules White granules 1 carton containing 50 packets NDC 0469-1230-50 NDC 0469-1330-50 Store and Dispense Store at 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. 16.4 Handling and Disposal Tacrolimus can cause fetal harm. PROGRAF capsules should not be opened or crushed. Wearing disposable gloves is recommended during dilution of the injection or when preparing the oral suspension in the hospital and when wiping any spills. Avoid inhalation or direct contact with skin or mucous membranes of the powder or granules contained in PROGRAF capsules and PROGRAF Granules, respectively. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures 1 .
<table width="100%"><col width="22%"/><col width="26%"/><col width="25%"/><col width="26%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">0.5 mg</content></paragraph><paragraph>(containing the equivalent of 0.5 mg anhydrous tacrolimus USP)</paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">1 mg</content></paragraph><paragraph>(containing the equivalent of 1 mg anhydrous tacrolimus USP)</paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">5 mg</content></paragraph><paragraph>(containing the equivalent of 5 mg anhydrous tacrolimus USP)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold"> Shape/color</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>oblong/light yellow</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>oblong/white</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>oblong/grayish red</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold"> Branding on</content></paragraph><paragraph><content styleCode="bold"> capsule cap/body</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph><renderMultiMedia ID="id437417429" referencedObject="C9AAABFA-4B6A-47E1-8349-523A0EA719D1"/>607</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph><renderMultiMedia ID="id764193592" referencedObject="F46F9466-B7BC-4211-BEA8-BE9394A46668"/>617</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph><renderMultiMedia ID="id944889064" referencedObject="FDB97DB8-12A5-4490-B78B-9B7533236760"/>657</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold"> 100 count bottle</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0469-0607-73</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0469-0617-73</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0469-0657-73</content></paragraph></td></tr></tbody></table>
="bold">NDC 0469-0607-73</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0469-0617-73</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0469-0657-73</content></paragraph></td></tr></tbody></table> <table width="100%"><col width="26%"/><col width="34%"/><col width="41%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">0.2 mg</content></paragraph><paragraph>(containing the equivalent of 0.2 mg anhydrous tacrolimus USP)</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">1 mg</content></paragraph><paragraph>(containing the equivalent of 1 mg anhydrous tacrolimus USP)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Shape/color</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>White granules</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>White granules</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">1 carton containing 50 packets</content></paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">NDC 0469-1230-50</content></paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">NDC 0469-1330-50</content></paragraph></td></tr></tbody></table>
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). 17.1 Administration Advise the patient or caregiver to: • Inspect their PROGRAF medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for PROGRAF. • Take PROGRAF at the same 12-hour intervals every day to achieve consistent blood concentrations. • Take PROGRAF consistently either with or without food because the presence and composition of food decreases the bioavailability of PROGRAF. • Not to eat grapefruit or drink grapefruit juice in combination with PROGRAF [see Drug Interactions ( 7.2 )]. • If the patient is receiving PROGRAF Granules, advise that the dose should be given immediately after preparation and not to save the dose for later. Advise the caregiver to carefully read the Instructions for Use. 17.2 Development of Lymphoma and Other Malignancies Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Warnings and Precautions ( 5.1 )] . 17.3 Increased Risk of Infection Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Warnings and Precautions ( 5.2 )] . 17.4 New Onset Diabetes After Transplant Inform patients that PROGRAF can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst, or hunger [see Warnings and Precautions ( 5.4 )] . 17.5 Nephrotoxicity Inform patients that PROGRAF can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions ( 5.5 )] . 17.6 Neurotoxicity Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions ( 5.6 )] . 17.7 Hyperkalemia Inform patients that PROGRAF can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions ( 5.7 )] . 17.8 Hypertension Inform patients that PROGRAF can cause high blood pressure which may require treatment with antihypertensive therapy. Advise patients to monitor their blood pressure [see Warnings and Precautions ( 5.8 )] . 17.9 Thrombotic Microangiopathy Inform patients that PROGRAF can cause blood clotting problems. The risk of this occurring increases when patients take PROGRAF and sirolimus or everolimus concomitantly, or when patients develop certain infections.
to monitor their blood pressure [see Warnings and Precautions ( 5.8 )] . 17.9 Thrombotic Microangiopathy Inform patients that PROGRAF can cause blood clotting problems. The risk of this occurring increases when patients take PROGRAF and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria. [see Warnings and Precautions ( 5.16 )] 17.10 Drug Interactions Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription medicines and nonprescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice [see Drug Interactions ( 7 )]. 17.11 Pregnancy, Lactation and Infertility Inform women of childbearing potential that PROGRAF can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations ( 8.1 , 8.2 , 8.3 )]. Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ [see Use in Specific Populations ( 8.1 )] . Based on animal studies, PROGRAF may affect fertility in males and females [see Nonclinical Toxicology ( 13.1 )]. 17.12 Myocardial Hypertrophy Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure). 17.13 Immunizations Inform patients that PROGRAF can interfere with the usual response to immunizations and that they should avoid live vaccines . [see Warnings and Precautions ( 5.14 )] . Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062 PROGRAF ® is a registered trademark of Astellas Pharma Inc. All other trademarks and registered trademarks are the property of their respective owners. 398977-PRG
Patient Information PROGRAF ® (PRO-graf) (tacrolimus) capsules, for oral use PROGRAF ® (PRO-graf) Granules (tacrolimus for oral suspension) Read this Patient Information before you start taking PROGRAF and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about PROGRAF? PROGRAF can cause serious side effects, including: • Increased risk of cancer. People who take PROGRAF have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma). • Increased risk of infection. PROGRAF is a medicine that affects your immune system. PROGRAF can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving PROGRAF that can cause death. Call your healthcare provider right away if you have any symptoms of an infection, including: o fever o sweats or chills o cough or flu-like symptoms o muscle aches o warm, red, or painful areas on your skin What is PROGRAF? • PROGRAF is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, heart, or lung transplant. • PROGRAF capsules and PROGRAF GRANULES are types of tacrolimus immediate-release drugs and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you. Who should not take PROGRAF? Do not take PROGRAF if you: • are allergic to tacrolimus or any of the ingredients in PROGRAF. See the end of this leaflet for a complete list of ingredients in PROGRAF. What should I tell my healthcare provider before taking PROGRAF? Before taking PROGRAF, tell your healthcare provider about all of your medical conditions, including if you: • plan to receive any vaccines. People taking PROGRAF should not receive live vaccines. • have or have had liver, kidney, or heart problems. • are pregnant or plan to become pregnant. PROGRAF can harm your unborn baby. o If you are able to become pregnant, you should use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you. o Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you. o There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with PROGRAF. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/ . • are breastfeeding or plan to breastfeed. PROGRAF passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking PROGRAF. • plan to have children. PROGRAF may affect the ability to have children in females and males (fertility problems).
nsplantpregnancyregistry.org/ . • are breastfeeding or plan to breastfeed. PROGRAF passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking PROGRAF. • plan to have children. PROGRAF may affect the ability to have children in females and males (fertility problems). Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine , including prescription and over-the-counter medicines, vitamins, natural, herbal, or nutritional supplements. Especially tell your healthcare provider if you take: • sirolimus (RAPAMUNE): You should not take PROGRAF if you take sirolimus • cyclosporine (GENGRAF, NEORAL, and SANDIMMUNE) • medicines called aminoglycosides that are used to treat bacterial infections • ganciclovir (CYTOVENE IV, VALCYTE) • amphotericin B (ABELCET, AMBISOME) • cisplatin • antiviral medicines called nucleoside reverse transcriptase inhibitors • antiviral medicines called protease inhibitors • water pill (diuretic) • medicine to treat high blood pressure • nelfinavir (VIRACEPT) • telaprevir (INCIVEK) • boceprevir • ritonavir (KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR) • letermovir (PREVYMIS) • ketoconazole • itraconazole (ONMEL, SPORANOX) • voriconazole (VFEND) • caspofungin (CANCIDAS) • clarithromycin (BIAXIN, BIAXIN XL, PREVPAC) • rifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE) • rifabutin (MYCOBUTIN) • amiodarone (NEXTERONE, PACERONE) • cannabidiol (EPIDIOLEX) Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. PROGRAF may affect the way other medicines work, and other medicines may affect how PROGRAF works. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take PROGRAF? • Take PROGRAF exactly as your healthcare provider tells you to take it. • Your healthcare provider will tell you how much PROGRAF to take and when to take it. Your healthcare provider may change your PROGRAF dose if needed. Do not stop taking or change your dose of PROGRAF without talking to your healthcare provider. • Take PROGRAF with or without food. • Take PROGRAF the same way every day. For example, if you choose to take PROGRAF with food, you should always take PROGRAF with food. • Take PROGRAF at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m. • Taking PROGRAF at the same time each day helps to keep the amount of medicine in your body at a steady level. • If you take too much PROGRAF, call your healthcare provider or go to the nearest hospital emergency room right away. PROGRAF capsules: • Do not open or crush PROGRAF capsules. PROGRAF Granules: • Children who have trouble swallowing capsules can be given PROGRAF Granules. • Give the dose of PROGRAF Granules right after preparing. Do not save prepared PROGRAF Granules as a liquid to take at a later time. • See the Instructions for Use at the end of this Patient Information for detailed instructions about how to mix and give PROGRAF Granules as a liquid in a glass cup or oral syringe. • If you get the granules or prepared oral suspension on your skin, wash the area well with soap and water. • If you get the granules or prepared oral suspension in your eyes, rinse with plain water. What should I avoid while taking PROGRAF? • While you take PROGRAF you should not receive any live vaccines. • Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).
ter. What should I avoid while taking PROGRAF? • While you take PROGRAF you should not receive any live vaccines. • Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF). • Do not eat grapefruit or drink grapefruit juice during treatment with PROGRAF. What are the possible side effects of PROGRAF? PROGRAF may cause serious side effects, including: • See “What is the most important information I should know about PROGRAF?” • problems from medicine errors. People who take PROGRAF have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as PROGRAF capsules or granules and cannot be substituted for each other. Check your PROGRAF when you get a new prescription and before you take it to make sure you have received PROGRAF capsules or PROGRAF Granules. • Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine. • high blood sugar (diabetes). Your healthcare provider may do blood tests to check for diabetes while you take PROGRAF. Call your healthcare provider right away if you have any symptoms of high blood sugar, including: o frequent urination o increased thirst or hunger o blurred vision o confusion o drowsiness o loss of appetite o fruity smell on your breath o nausea, vomiting, or stomach pain • kidney problems. Kidney problems are a serious and common side effect of PROGRAF. Your healthcare provider may do blood tests to check your kidney function while you take PROGRAF. • nervous system problems. Nervous system problems are a serious and common side effect of PROGRAF. Call your healthcare provider right away if you get any of these symptoms while taking PROGRAF. These could be signs of a serious nervous system problem: o headache o confusion o seizures o changes in your vision o changes in behavior o coma o tremors o numbness and tingling • high levels of potassium in your blood. Your healthcare provider may do blood tests to check your potassium level while you take PROGRAF. • high blood pressure. High blood pressure is a serious and common side effect of PROGRAF. Your healthcare provider will monitor your blood pressure while you take PROGRAF and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home. • changes in the electrical activity of your heart (QT prolongation). • heart problems (myocardial hypertrophy). Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking PROGRAF: o shortness of breath o chest pain o feel lightheaded o feel faint • severe low red blood cell count (anemia). • blood clotting problems: Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase.
problems: Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase. The most common side effects of PROGRAF in people who have received a kidney, liver, heart, or lung transplant are: • infections in general, including cytomegalovirus (cmv) infection • tremors (shaking of the body) • constipation • diarrhea • headache • stomach pain • trouble sleeping • nausea • high blood sugar (diabetes) • low levels of magnesium in your blood • low levels of phosphate in your blood • swelling of the hands, legs, ankles, or feet • weakness • pain • high levels of fat in your blood • high levels of potassium in your blood • low red blood cell count (anemia) • low white blood cell count • fever • numbness or tingling in your hands and feet • inflammation of your airway (bronchitis) • fluid around your heart Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of PROGRAF. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store PROGRAF? PROGRAF capsules • Store PROGRAF capsules at room temperature between 68°F to 77°F (20°C to 25°C). PROGRAF Granules • Store PROGRAF Granules packets at room temperature between 68°F to 77°F (20°C to 25°C). Keep PROGRAF and all medicines out of the reach of children. General information about the safe and effective use of PROGRAF. • Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROGRAF for a condition for which it was not prescribed. Do not give PROGRAF to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PROGRAF that is written for health professionals. • This Patient Information leaflet summarizes the most important information about PROGRAF. If you would like more information, talk to your healthcare provider. What are the ingredients in PROGRAF? Active ingredient: tacrolimus Inactive ingredients: PROGRAF capsules: croscarmellose sodium, hypromellose, lactose monohydrate, and magnesium stearate. The 0.5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide. The 1 mg capsule shell contains gelatin and titanium dioxide. The 5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide. PROGRAF Granules: croscarmellose sodium, hypromellose, and lactose monohydrate. Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062 PROGRAF ® is a registered trademark of Astellas Pharma Inc. All other trademarks and registered trademarks are the property of their respective owners. 398977-PRG For more information, go to www.astellas.com/us or call 1-800-727-7003. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 08/2023
<table width="100%"><col width="2%"/><col width="41%"/><col width="57%"/><tbody><tr><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Patient Information</content></paragraph><paragraph>PROGRAF<sup>®</sup> (PRO-graf) (tacrolimus) capsules, for oral use</paragraph><paragraph>PROGRAF<sup>®</sup> (PRO-graf) Granules (tacrolimus for oral suspension)</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Read this Patient Information before you start taking PROGRAF and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. </paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about PROGRAF?</content></paragraph><paragraph><content styleCode="bold">PROGRAF can cause serious side effects, including:</content></paragraph><list listType="unordered"><item><caption>•</caption><content styleCode="bold">Increased risk of cancer. </content>People who take PROGRAF have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).</item><item><caption>•</caption><content styleCode="bold">Increased risk of infection. </content>PROGRAF is a medicine that affects your immune system. PROGRAF can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving PROGRAF that can cause death. <content styleCode="bold">Call your healthcare provider right away if you have any symptoms of an infection, including:</content></item></list></td></tr><tr><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Botrule " valign="top"><list listType="unordered"><item><caption>o</caption>fever</item><item><caption>o</caption>sweats or chills</item><item><caption>o</caption>cough or flu-like symptoms</item></list></td><td styleCode="Rrule Botrule " valign="top"><list listType="unordered"><item><caption>o</caption>muscle aches</item><item><caption>o</caption>warm, red, or painful areas on your skin</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is PROGRAF?</content></paragraph><list listType="unordered"><item><caption>•</caption>PROGRAF is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, heart, or lung transplant. </item><item><caption>•</caption>PROGRAF capsules and PROGRAF GRANULES are types of tacrolimus immediate-release drugs and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Who should not take PROGRAF?</content></paragraph><paragraph><content styleCode="bold">Do not take PROGRAF if you:</content></paragraph><list listType="unordered"><item><caption>•</caption>are allergic to tacrolimus or any of the ingredients in PROGRAF.
Botrule " valign="top"><paragraph><content styleCode="bold">Who should not take PROGRAF?</content></paragraph><paragraph><content styleCode="bold">Do not take PROGRAF if you:</content></paragraph><list listType="unordered"><item><caption>•</caption>are allergic to tacrolimus or any of the ingredients in PROGRAF. See the end of this leaflet for a complete list of ingredients in PROGRAF.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I tell my healthcare provider before taking PROGRAF?</content></paragraph><paragraph><content styleCode="bold">Before taking PROGRAF, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item><caption>•</caption>plan to receive any vaccines. People taking PROGRAF should not receive live vaccines. </item><item><caption>•</caption>have or have had liver, kidney, or heart problems.</item><item><caption>•</caption>are pregnant or plan to become pregnant. PROGRAF can harm your unborn baby.<list listType="unordered"><item><caption>o</caption>If you are able to become pregnant, you should use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you.</item><item><caption>o</caption>Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you. </item><item><caption>o</caption>There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with PROGRAF. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to <linkHtml href="https://www.transplantpregnancyregistry.org/">https://www.transplantpregnancyregistry.org/</linkHtml>.</item></list></item><item><caption>•</caption>are breastfeeding or plan to breastfeed. PROGRAF passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking PROGRAF.</item><item><caption>•</caption>plan to have children.
pregnancyregistry.org/</linkHtml>.</item></list></item><item><caption>•</caption>are breastfeeding or plan to breastfeed. PROGRAF passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking PROGRAF.</item><item><caption>•</caption>plan to have children. PROGRAF may affect the ability to have children in females and males (fertility problems).</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine</content>, including prescription and over-the-counter medicines, vitamins, natural, herbal, or nutritional supplements.</paragraph><paragraph><content styleCode="bold">Especially tell your healthcare provider if you take:</content></paragraph><list listType="unordered"><item><caption>•</caption>sirolimus (RAPAMUNE): You should not take PROGRAF if you take sirolimus </item><item><caption>•</caption>cyclosporine (GENGRAF, NEORAL, and SANDIMMUNE)</item><item><caption>•</caption>medicines called aminoglycosides that are used to treat bacterial infections</item><item><caption>•</caption>ganciclovir (CYTOVENE IV, VALCYTE)</item><item><caption>•</caption>amphotericin B (ABELCET, AMBISOME)</item><item><caption>•</caption>cisplatin</item><item><caption>•</caption>antiviral medicines called nucleoside reverse transcriptase inhibitors </item><item><caption>•</caption>antiviral medicines called protease inhibitors </item><item><caption>•</caption>water pill (diuretic)</item><item><caption>•</caption>medicine to treat high blood pressure </item><item><caption>•</caption>nelfinavir (VIRACEPT)</item><item><caption>•</caption>telaprevir (INCIVEK)</item><item><caption>•</caption>boceprevir </item><item><caption>•</caption>ritonavir (KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR)</item><item><caption>•</caption>letermovir (PREVYMIS)</item><item><caption>•</caption>ketoconazole </item><item><caption>•</caption>itraconazole (ONMEL, SPORANOX)</item><item><caption>•</caption>voriconazole (VFEND) </item><item><caption>•</caption>caspofungin (CANCIDAS)</item><item><caption>•</caption>clarithromycin (BIAXIN, BIAXIN XL, PREVPAC)</item><item><caption>•</caption>rifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE)</item><item><caption>•</caption>rifabutin (MYCOBUTIN) </item><item><caption>•</caption>amiodarone (NEXTERONE, PACERONE) </item><item><caption>•</caption>cannabidiol (EPIDIOLEX)</item></list><paragraph>Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above.</paragraph><paragraph>PROGRAF may affect the way other medicines work, and other medicines may affect how PROGRAF works.</paragraph><paragraph>Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take PROGRAF?</content></paragraph><list listType="unordered"><item><caption>•</caption>Take PROGRAF exactly as your healthcare provider tells you to take it.</item><item><caption>•</caption>Your healthcare provider will tell you how much PROGRAF to take and when to take it.</item><item><caption> </caption>Your healthcare provider may change your PROGRAF dose if needed.
m><caption>•</caption>Take PROGRAF exactly as your healthcare provider tells you to take it.</item><item><caption>•</caption>Your healthcare provider will tell you how much PROGRAF to take and when to take it.</item><item><caption> </caption>Your healthcare provider may change your PROGRAF dose if needed. <content styleCode="bold">Do not </content>stop taking or change your dose of PROGRAF without talking to your healthcare provider.</item><item><caption>•</caption>Take PROGRAF with or without food.</item><item><caption>•</caption>Take PROGRAF the same way every day. For example, if you choose to take PROGRAF with food, you should always take PROGRAF with food.</item><item><caption>•</caption>Take PROGRAF at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m.</item><item><caption>•</caption>Taking PROGRAF at the same time each day helps to keep the amount of medicine in your body at a steady level.</item><item><caption>•</caption>If you take too much PROGRAF, call your healthcare provider or go to the nearest hospital emergency room right away.</item></list><paragraph><content styleCode="bold">PROGRAF capsules:</content></paragraph><list listType="unordered"><item><caption>•</caption><content styleCode="bold">Do not</content> open or crush PROGRAF capsules.</item></list><paragraph><content styleCode="bold">PROGRAF Granules:</content></paragraph><list listType="unordered"><item><caption>•</caption>Children who have trouble swallowing capsules can be given PROGRAF Granules.</item><item><caption>•</caption>Give the dose of PROGRAF Granules right after preparing. Do not save prepared PROGRAF Granules as a liquid to take at a later time. </item><item><caption>•</caption><content styleCode="bold">See the Instructions for Use at the end of this Patient Information</content> for detailed instructions about how to mix and give PROGRAF Granules as a liquid in a glass cup or oral syringe.</item><item><caption>•</caption>If you get the granules or prepared oral suspension on your skin, wash the area well with soap and water. </item><item><caption>•</caption>If you get the granules or prepared oral suspension in your eyes, rinse with plain water.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I avoid while taking PROGRAF?</content></paragraph><list listType="unordered"><item><caption>•</caption>While you take PROGRAF you should not receive any live vaccines. </item><item><caption>•</caption>Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).</item><item><caption>•</caption><content styleCode="bold">Do not</content> eat grapefruit or drink grapefruit juice during treatment with PROGRAF.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of PROGRAF?</content></paragraph><paragraph><content styleCode="bold">PROGRAF may cause serious side effects, including:</content></paragraph><list listType="unordered"><item><caption>•</caption>See<content styleCode="bold"> “What is the most important information I should know about PROGRAF?”</content></item><item><caption>•</caption><content styleCode="bold">problems from medicine errors. </content>People who take PROGRAF have sometimes been given the wrong type of tacrolimus product.
on>See<content styleCode="bold"> “What is the most important information I should know about PROGRAF?”</content></item><item><caption>•</caption><content styleCode="bold">problems from medicine errors. </content>People who take PROGRAF have sometimes been given the wrong type of tacrolimus product. <content styleCode="bold">Tacrolimus extended-release medicines are not the same as PROGRAF capsules or granules </content>and cannot be substituted for each other. <content styleCode="bold">Check your PROGRAF when you get a new prescription and before you take it to make sure you have received PROGRAF capsules or PROGRAF Granules.</content></item><item><caption>•</caption>Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine. </item><item><caption>•</caption><content styleCode="bold">high blood sugar (diabetes). </content>Your healthcare provider may do blood tests to check for diabetes while you take PROGRAF. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:</item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption>o</caption>frequent urination</item><item><caption>o</caption>increased thirst or hunger</item><item><caption>o</caption>blurred vision</item><item><caption>o</caption>confusion</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption>o</caption>drowsiness</item><item><caption>o</caption>loss of appetite</item><item><caption>o</caption>fruity smell on your breath</item><item><caption>o</caption>nausea, vomiting, or stomach pain</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption>•</caption><content styleCode="bold">kidney problems. </content>Kidney problems are a serious and common side effect of PROGRAF. Your healthcare provider may do blood tests to check your kidney function while you take PROGRAF. </item><item><caption>•</caption><content styleCode="bold">nervous system problems. </content>Nervous system problems are a serious and common side effect of PROGRAF. Call your healthcare provider right away if you get any of these symptoms while taking PROGRAF. These could be signs of a serious nervous system problem:</item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption>o</caption>headache</item><item><caption>o</caption>confusion</item><item><caption>o</caption>seizures</item><item><caption>o</caption>changes in your vision</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption>o</caption>changes in behavior</item><item><caption>o</caption>coma</item><item><caption>o</caption>tremors</item><item><caption>o</caption>numbness and tingling</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption>•</caption><content styleCode="bold">high levels of potassium in your blood. </content>Your healthcare provider may do blood tests to check your potassium level while you take PROGRAF.</item><item><caption>•</caption><content styleCode="bold">high blood pressure.</content> High blood pressure is a serious and common side effect of PROGRAF. Your healthcare provider will monitor your blood pressure while you take PROGRAF and may prescribe blood pressure medicine for you, if needed.
take PROGRAF.</item><item><caption>•</caption><content styleCode="bold">high blood pressure.</content> High blood pressure is a serious and common side effect of PROGRAF. Your healthcare provider will monitor your blood pressure while you take PROGRAF and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.</item><item><caption>•</caption><content styleCode="bold">changes in the electrical activity of your heart (QT prolongation).</content></item><item><caption>•</caption><content styleCode="bold">heart problems (myocardial hypertrophy).</content> Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking PROGRAF:</item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption>o</caption>shortness of breath</item><item><caption>o</caption>chest pain</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption>o</caption>feel lightheaded</item><item><caption>o</caption>feel faint</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption>•</caption><content styleCode="bold">severe low red blood cell count (anemia). </content></item><item><caption>•</caption><content styleCode="bold">blood clotting problems:</content> Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination.
t></item><item><caption>•</caption><content styleCode="bold">blood clotting problems:</content> Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">The most common side effects of PROGRAF in people who have received a kidney, liver, heart, or lung transplant are:</content></paragraph></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption>•</caption>infections in general, including cytomegalovirus (cmv) infection</item><item><caption>•</caption>tremors (shaking of the body)</item><item><caption>•</caption>constipation</item><item><caption>•</caption>diarrhea</item><item><caption>•</caption>headache</item><item><caption>•</caption>stomach pain</item><item><caption>•</caption>trouble sleeping</item><item><caption>•</caption>nausea</item><item><caption>•</caption>high blood sugar (diabetes)</item><item><caption>•</caption>low levels of magnesium in your blood</item><item><caption>•</caption>low levels of phosphate in your blood</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption>•</caption>swelling of the hands, legs, ankles, or feet</item><item><caption>•</caption>weakness</item><item><caption>•</caption>pain</item><item><caption>•</caption>high levels of fat in your blood</item><item><caption>•</caption>high levels of potassium in your blood</item><item><caption>•</caption>low red blood cell count (anemia)</item><item><caption>•</caption>low white blood cell count</item><item><caption>•</caption>fever</item><item><caption>•</caption>numbness or tingling in your hands and feet</item><item><caption>•</caption>inflammation of your airway (bronchitis)</item><item><caption>•</caption>fluid around your heart</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</paragraph><paragraph>These are not all the possible side effects of PROGRAF. For more information, ask your healthcare provider or pharmacist.</paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store PROGRAF?</content></paragraph><paragraph><content styleCode="bold">PROGRAF capsules</content></paragraph><list listType="unordered"><item><caption>•</caption>Store PROGRAF capsules at room temperature between 68°F to 77°F (20°C to 25°C).
<paragraph><content styleCode="bold">How should I store PROGRAF?</content></paragraph><paragraph><content styleCode="bold">PROGRAF capsules</content></paragraph><list listType="unordered"><item><caption>•</caption>Store PROGRAF capsules at room temperature between 68°F to 77°F (20°C to 25°C). </item></list><paragraph><content styleCode="bold">PROGRAF Granules</content></paragraph><list listType="unordered"><item><caption>•</caption>Store PROGRAF Granules packets at room temperature between 68°F to 77°F (20°C to 25°C).</item></list><paragraph><content styleCode="bold">Keep PROGRAF and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of PROGRAF.</content></paragraph><list listType="unordered"><item><caption>•</caption>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROGRAF for a condition for which it was not prescribed. Do not give PROGRAF to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PROGRAF that is written for health professionals. </item><item><caption>•</caption>This Patient Information leaflet summarizes the most important information about PROGRAF. If you would like more information, talk to your healthcare provider.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in PROGRAF?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content> tacrolimus</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content></paragraph><paragraph>PROGRAF capsules: croscarmellose sodium, hypromellose, lactose monohydrate, and magnesium stearate. The 0.5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide. The 1 mg capsule shell contains gelatin and titanium dioxide. The 5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide.</paragraph><paragraph>PROGRAF Granules: croscarmellose sodium, hypromellose, and lactose monohydrate.</paragraph><paragraph>Distributed by: <content styleCode="bold">Astellas Pharma US, Inc. </content>Northbrook, IL 60062</paragraph><paragraph>PROGRAF<sup>®</sup> is a registered trademark of Astellas Pharma Inc. All other trademarks and registered trademarks are the property of their respective owners.</paragraph><paragraph>398977-PRG </paragraph><paragraph>For more information, go to www.astellas.com/us or call 1-800-727-7003.</paragraph></td></tr></tbody></table>
Instructions for Use PROGRAF ® Granules (PRO-graf) (tacrolimus for oral suspension) Your healthcare provider has prescribed PROGRAF ® Granules, which comes in individual packets that will need to be mixed with water before giving the medicine to your child. Read this Instructions for Use and the Patient Information for the first time and each time you get a refill of PROGRAF Granules (tacrolimus for oral suspension). There may be new information. This Instructions for Use does not take the place of talking to your child’s healthcare provider about their medical condition or treatment. Ask the healthcare provider if you have any questions about how to mix or give a dose of PROGRAF Granules the right way. Important information: These instructions are for preparing PROGRAF Granules only. These instructions should not be used for PROGRAF capsules. • Mix PROGRAF Granules in water to make an oral suspension. • Give all of the prepared oral suspension to your child right away after preparing. Do not save the prepared oral suspension for later use. • Use glass or metal materials to prepare your child’s dose of PROGRAF Granules. o Do not use any plastic (PVC) materials to prepare PROGRAF Granules. The granules will stick to a plastic container and your child may not receive their full dose. • Do not breathe in (inhale) or let the granules in PROGRAF or the prepared oral suspension come in contact with your skin or eyes. o If you get the granules or the prepared oral suspension on your skin, wash the area well with soap and water. o If you get the granules or the prepared oral suspension in your eyes, rinse with plain water. If you spill the granules, wipe the surface with a wet paper towel. If you spill the prepared oral suspension, dry the area with a dry paper towel and then wipe the area with a wet paper towel. Throw away the paper towels in the trash and wash your hands well with soap and water. For each dose of PROGRAF Granules mixed with water that will be given using a glass cup, you will need the following supplies (See Figure A): • Carton containing PROGRAF Granules packets. Follow the instructions on the carton for the number of packets your child’s healthcare provider has prescribed for each dose. • paper towels • pair of scissors • metal stirring spoon • measuring device • 1 small clean glass cup (plastic containers should not be used) • container with drinking water Figure A Step 1 Choose a clean flat work surface. Place a clean paper towel on the work surface. Place the supplies to prepare the dose on the paper towel. Step 2 Wash and dry your hands. Step 3 Remove the prescribed number of PROGRAF Granules packets from the carton. Step 4 Using a pair of scissors, cut along the dotted line on 1 PROGRAF Granules packet to open it. Step 5 Empty all of the granules in the packet into the glass cup. Check for any remaining granules in the packet and empty these into the glass cup. Step 6 If more than 1 packet of PROGRAF Granules is needed for your child’s prescribed dose, repeat Steps 4 and 5 using the number of packets needed for the prescribed dose. Step 7 Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the glass cup containing the granules. Step 8 Gently stir the granules and water in the glass cup with a metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the water. Step 9 Give the granules and water suspension in the glass cup to your child.
drinking water to the glass cup containing the granules. Step 8 Gently stir the granules and water in the glass cup with a metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the water. Step 9 Give the granules and water suspension in the glass cup to your child. Make sure your child drinks all of the medicine in the cup. Give all of the medicine to your child right away after preparing. Do not save the medicine for later use. Step 10 To make sure all of the medicine is given to your child, refill the glass cup with the same amount of water used in Step 7. Step 11 Gently swirl the glass cup to mix any remaining granules. Step 12 Give all of the medicine in the cup to the child. Step 13 Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands. For each dose of PROGRAF Granules (tacrolimus for oral suspension) mixed with water that will be drawn up and given using an oral syringe, you will need the following supplies (See Figure B): • Carton containing PROGRAF Granules packets. Follow the instructions on the carton for the number of packets your child’s healthcare provider has prescribed for each dose. • paper towels • pair of scissors • metal stirring spoon • measuring device • 1 small clean glass cup (plastic containers should not be used) • container with drinking water • 1 non-PVC oral syringe (ask your pharmacist for the oral syringe you should use) Figure B Step 1 Choose a clean flat work surface. Place a clean paper towel on the work surface. Place the supplies to prepare the dose on the paper towel. Step 2 Wash and dry your hands. Step 3 Remove the prescribed number of PROGRAF Granules packets from the carton. Step 4 Using a pair of scissors, cut along the dotted line on 1 PROGRAF Granules packet to open it. Step 5 Empty all of the granules in the packet into the glass cup. Check for any remaining granules in the packet and empty these into the glass cup. Step 6 If more than 1 packet of PROGRAF Granules is needed for your child’s prescribed dose, repeat Steps 4 and 5 using the number of packets needed for the prescribed dose. Step 7 Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the glass cup containing the granules. Step 8 Gently stir the granules and drinking water in the glass cup with a metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the drinking water. Step 9 Insert the tip of the oral syringe into the glass cup. Pull back on the plunger of the oral syringe to draw up the suspension. Step 10 Place the tip of the oral syringe in your child’s mouth along the inner cheek. Slowly push the plunger all the way down to give your child all of the medicine in the oral syringe. Repeat Steps 9 and 10 until the glass cup is empty. Give all of the medicine to your child right away after preparing. Do not save the medicine for later use. Step 11 To make sure all of the medicine is given to your child, refill the glass cup with the same amount of drinking water used in Step 7. Step 12 Gently swirl the glass cup to mix any remaining granules. Step 13 Repeat Steps 9 and 10 until the glass cup is empty. Step 14 Rinse the plunger and barrel of the syringe well with drinking water and dry well before storing the oral syringe. Step 15 Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands. How should I store PROGRAF Granules packets? Store PROGRAF Granules packets at room temperature between 68°F to 77°F (20°C to 25°C). Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. Keep PROGRAF Granules and all medicine out of the reach of children.
ore PROGRAF Granules packets? Store PROGRAF Granules packets at room temperature between 68°F to 77°F (20°C to 25°C). Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. Keep PROGRAF Granules and all medicine out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062 PROGRAF ® is a registered trademark of Astellas Pharma Inc. 341124-PRG Revised: 11/2022 Figure A Step 3 Step 4 Step 5 Step 7 Step 8 Step 9 Figure B Step 3 Step 4 Step 5 Step 7 Step 8 Step 9 Step 10
<table width="76.56%"><col width="95%"/><tbody><tr><td align="center" styleCode="Botrule Toprule " valign="top"><renderMultiMedia ID="id-1274944139" referencedObject="ID_17f0921a-57b0-4234-a861-33a3dfa3fc1e"/></td></tr></tbody></table>
<table width="76.56%"><col width="95%"/><tbody><tr><td align="center" styleCode="Botrule Toprule " valign="top"><renderMultiMedia ID="id-1274944139" referencedObject="ID_17f0921a-57b0-4234-a861-33a3dfa3fc1e"/></td></tr></tbody></table> <table width="105.56%"><col width="9%"/><col width="38%"/><col width="53%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Step 1</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Choose a clean flat work surface. Place a clean paper towel on the work surface. Place the supplies to prepare the dose on the paper towel. </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 2</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Wash and dry your hands.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 3</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Remove the prescribed number of PROGRAF Granules packets from the carton.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><renderMultiMedia ID="id1664822285" referencedObject="ID_29eef096-428a-41cb-9427-154c767d2ed1"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 4</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Using a pair of scissors, cut along the dotted line on 1 PROGRAF Granules packet to open it.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><renderMultiMedia ID="id-1819790658" referencedObject="E722B9EE-5524-4D4C-A548-CF5E6D2FA5C3"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 5</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Empty all of the granules in the packet into the glass cup. Check for any remaining granules in the packet and empty these into the glass cup.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><renderMultiMedia ID="id518742511" referencedObject="A2DB438A-8940-42F1-B19D-795614CDDAA6"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 6</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>If more than 1 packet of PROGRAF Granules is needed for your child’s prescribed dose, repeat Steps 4 and 5 using the number of packets needed for the prescribed dose.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 7</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the glass cup containing the granules.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><renderMultiMedia ID="id549035501" referencedObject="ID_187703fc-01f6-4f66-8ea5-e0d3e20f1056"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 8</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gently stir the granules and water in the glass cup with a metal stirring spoon. The granules will not completely dissolve.
/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 8</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gently stir the granules and water in the glass cup with a metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the water.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><renderMultiMedia ID="id863712973" referencedObject="ID_2387964c-4c89-4238-968a-14d4c23c2af5"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 9</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Give the granules and water suspension in the glass cup to your child. Make sure your child drinks all of the medicine in the cup.</paragraph><paragraph>Give all of the medicine to your child right away after preparing. <content styleCode="bold">Do not</content> save the medicine for later use.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><renderMultiMedia ID="id-1178811645" referencedObject="ID_2aa0ed2a-ed50-447a-8884-147c4fd55b05"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 10</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>To make sure all of the medicine is given to your child, refill the glass cup with the same amount of water used in Step 7.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 11</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gently swirl the glass cup to mix any remaining granules.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 12</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Give all of the medicine in the cup to the child.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Step 13</content></paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands.</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"/></tr></tbody></table>
n="top"><paragraph><content styleCode="bold">Step 13</content></paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands.</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"/></tr></tbody></table> <table width="96.54%"><col width="10%"/><col width="40%"/><col width="50%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Step 1</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Choose a clean flat work surface. Place a clean paper towel on the work surface. Place the supplies to prepare the dose on the paper towel.</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 2</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Wash and dry your hands.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 3</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Remove the prescribed number of PROGRAF Granules packets from the carton.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><renderMultiMedia ID="id247864569" referencedObject="ID_8dc6da8a-081d-4df3-bc3d-c960692c569f"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 4</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Using a pair of scissors, cut along the dotted line on 1 PROGRAF Granules packet to open it.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><renderMultiMedia ID="id-1214580070" referencedObject="C3590410-FCAE-4DB7-BC0B-5FA0F3C76156"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 5 </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Empty all of the granules in the packet into the glass cup. Check for any remaining granules in the packet and empty these into the glass cup. </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><renderMultiMedia ID="id-88923255" referencedObject="AA4F5726-B8AD-4933-9E47-F08E158D2EDD"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 6</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>If more than 1 packet of PROGRAF Granules is needed for your child’s prescribed dose, repeat Steps 4 and 5 using the number of packets needed for the prescribed dose.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 7</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the glass cup containing the granules.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><renderMultiMedia ID="id-1822190021" referencedObject="ID_0c7ecf9d-eb7a-4b89-8c7a-045be2060e09"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 8</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gently stir the granules and drinking water in the glass cup with a metal stirring spoon. The granules will not completely dissolve.
tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 8</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gently stir the granules and drinking water in the glass cup with a metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the drinking water.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><renderMultiMedia ID="id-916936612" referencedObject="F875BACC-F3F9-4070-8339-18096B6978CE"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 9</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Insert the tip of the oral syringe into the glass cup.</paragraph><paragraph>Pull back on the plunger of the oral syringe to draw up the suspension.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><renderMultiMedia ID="id1264640926" referencedObject="CF0E87E9-709B-4EEA-AF2E-890C486123A2"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 10</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Place the tip of the oral syringe in your child’s mouth along the inner cheek. Slowly push the plunger all the way down to give your child <content styleCode="bold">all</content> of the medicine in the oral syringe. Repeat Steps 9 and 10 until the glass cup is empty. Give all of the medicine to your child right away after preparing. <content styleCode="bold">Do not</content> save the medicine for later use.</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><renderMultiMedia ID="id-1734084650" referencedObject="ID_8cc1ee64-df47-4557-b43e-c50d3cce241c"/></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 11</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>To make sure all of the medicine is given to your child, refill the glass cup with the same amount of drinking water used in Step 7.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 12</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gently swirl the glass cup to mix any remaining granules. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 13</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Repeat Steps 9 and 10 until the glass cup is empty.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Step 14</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rinse the plunger and barrel of the syringe well with drinking water and dry well before storing the oral syringe.</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Step 15</content></paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands.</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"/></tr></tbody></table>
WARNING: MALIGNANCIES AND SERIOUS INFECTIONS Increased risk for developing serious infections and malignancies with tacrolimus capsules or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 ) WARNING: MALIGNANCIES AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Increased risk for developing serious infections and malignancies with tacrolimus capsules or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 )
1 INDICATIONS AND USAGE Tacrolimus capsules are a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, or heart transplants, in combination with other immunosuppressants. ( 1.1 ) 1.1 Prophylaxis of Organ Rejection in Kidney, Liver, or Heart Transplant Tacrolimus capsules are indicated for the prophylaxis of organ rejection, in adult and pediatric patients receiving allogeneic kidney transplant [see Clinical Studies (14.1) ] , liver transplant [see Clinical Studies (14.2) ] , and heart transplant [see Clinical Studies (14.3) ] , in combination with other immunosuppressants. Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
2 DOSAGE AND ADMINISTRATION Administer capsules consistently with or without food. () Therapeutic drug monitoring is recommended. (, 2.6 ) Avoid eating grapefruit or drinking grapefruit juice. () See dosage adjustments for African-American patients ( 2.2 ), hepatic and renal impaired. ( 2.4 , 2.5 ) For complete dosing information, see Full Prescribing Information. MMF = Mycophenolate mofetil ADULT Patient Population Initial Oral Dosage Whole Blood Trough Concentration Range Kidney Transplant With azathioprine 0.2 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL With MMF/IL-2 receptor antagonist 0.1 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 4-11 ng/mL Liver Transplant With corticosteroids only 0.1-0.15 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant With azathioprine or MMF 0.075 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL PEDIATRIC Patient Population Initial Oral Dosage Whole Blood Trough Concentration Range Kidney Transplant 0.3 mg/kg/day capsules divided into two doses, every 12 hours. Month 1-12: 5-20 ng/mL Liver Transplant 0.15-0.2 mg/kg/day capsules divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant 0.3 mg/kg/day 2 capsules divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL 2. Dose at 0.1 mg/kg/day if antibody induction treatment is administered. 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) ] . Oral Formulation (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 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 Capsules If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated.
toring (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 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 and 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 capsule 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 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL With MMF/IL-2 receptor antagonist In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL during month 1-3 and 5-12 ng/mL during month 4-12 [see Clinical Studies (14.1)] . 0.1 mg/kg/day, divided in two doses, administered every 12 hours Month 1-12: 4-11 ng/mL Liver Transplant With corticosteroids only 0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant With azathioprine or MMF 0.075 mg/kg/day, divided in two doses, administered every 12 hours Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 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 Caucasian N = 114 African-American N = 56 Time After Transplant 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 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 Dosage Recommendations for Pediatric Kidney, Liver, or Heart Transplant Patients Oral Formulation (Capsules) Pediatric patients, in general, need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole blood trough concentration range are shown in Table 3. Perform TDM to ensure that patients are within the ranges listed in Table 3. Table 3.
ses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole blood trough concentration range are shown in Table 3. Perform TDM to ensure that patients are within the ranges listed in Table 3. Table 3. Summary of Initial Tacrolimus Capsule Dosage Recommendations and Whole Blood Trough Concentration Range in Children Patient Population Initial Tacrolimus Capsule Dosing Whole Blood Trough Concentration Range Pediatric kidney transplant patients 0.3 mg/kg/day capsules divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Pediatric liver transplant patients See Clinical Studies (14.2), Liver Transplantation. 0.15-0.2 mg/kg/day capsules divided in two doses, administered every 12 hours Month 1-12: 5-20 ng/mL Pediatric heart transplant patients 0.3 mg/kg/day Dose at 0.1 mg/kg/day if antibody induction treatment is administered. capsules divided in two doses, administered every 12 hours. Month 1-12: 5-20 ng/mL For conversion of pediatric patients from tacrolimus for oral suspension to tacrolimus capsules or from tacrolimus capsules to tacrolimus for oral suspension, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration (2.6) ] . Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Dosage Modification for Patients with Renal Impairment Due to its potential for nephrotoxicity, consider dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant, and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required. In kidney transplant patients with post-operative oliguria, the initial dose of tacrolimus capsules should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration (2.2) , Warnings and Precautions (5.5) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] . 2.5 Dosage Modification for Patients with Hepatic Impairment Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh ≥ 10) may require lower doses of tacrolimus capsules. Close monitoring of blood concentrations is warranted. The use of tacrolimus capsules in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. These patients should be monitored closely, and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.2) , Warnings and Precautions (5.5) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ]. 2.6 Therapeutic Drug Monitoring Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments, and compliance. Whole blood trough concentration range can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time.
f rejection, toxicity, dose adjustments, and compliance. Whole blood trough concentration range can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation. The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure. Methods commonly used for the assay of tacrolimus include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore, assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer, they should be deep frozen at -20°C. One study showed drug recovery > 90% for samples stored at -20°C for 6 months, with reduced recovery observed after 6 months.
3 DOSAGE FORMS AND STRENGTHS Tacrolimus Capsules, USP are available containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus, USP. The 0.5 mg capsules are hard-shell gelatin capsules with a light orange opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLAN over 2045 in black ink on both the cap and the body. The 1 mg capsules are hard-shell gelatin capsules with a light blue opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLAN over 2046 in black ink on both the cap and the body. The 5 mg capsules are hard-shell gelatin capsules with a rubine red opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLAN over 2047 in black ink on both the cap and the body. Capsules: 0.5 mg, 1 mg and 5 mg ( 3 )
4 CONTRAINDICATIONS 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) ] . Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 )
5 WARNINGS AND PRECAUTIONS Not Interchangeable with Extended-Release Tacrolimus Products - Medication Errors: Instruct patients or caregivers to recognize the appearance of tacrolimus capsules. ( 5.3 ) New Onset Diabetes After Transplant: Monitor blood glucose. ( 5.4 ) Nephrotoxicity (acute and/or chronic): Reduce the dose; use caution with other nephrotoxic drugs. ( 5.5 ) Neurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue tacrolimus capsules. ( 5.6 ) Hyperkalemia: Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia. ( 5.7 ) Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions. ( 5.8 ) Anaphylactic Reactions with IV formulation: Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis. ( 5.9 ) Not recommended for use with sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions. ( 5.10 ) Myocardial Hypertrophy: Consider dose reduction/discontinuation. ( 5.13 ) Immunizations: Avoid live vaccines. ( 5.14 ) Pure Red Cell Aplasia: Consider discontinuation of tacrolimus. ( 5.15 ) Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.16 ) 5.1 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including tacrolimus, are at increased 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. As usual for patients with increased risk for skin cancer, examine patients for skin changes; exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein-Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment. 5.2 Serious Infections Patients receiving immunosuppressants, including tacrolimus, are at increased 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 (PVAN), mostly due to BK virus infection JC virus-associated progressive multifocal leukoencephalopathy (PML) Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing 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) ] .
ransplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing 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 Not Interchangeable with Extended-Release Tacrolimus Products - Medication Errors Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or overexposure to tacrolimus. Tacrolimus capsules are not interchangeable or substitutable for tacrolimus extended-release products. 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 dosage forms [see Dosage Forms and Strengths (3) ] and to confirm with the healthcare provider if a different product is dispensed. 5.4 New Onset Diabetes After Transplant Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, or heart transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using tacrolimus [see Adverse Reactions (6.1) ] . 5.5 Nephrotoxicity Due to Tacrolimus and Drug Interactions Tacrolimus, 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. Nephrotoxicity was reported in clinical trials [see Adverse Reactions (6.1) ] . 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 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 doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions (7.2) ] . 5.6 Neurotoxicity Tacrolimus 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 if neurotoxicity occurs. 5.7 Hyperkalemia Hyperkalemia has been reported with tacrolimus use. Serum potassium levels should be monitored.
ed with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of tacrolimus if neurotoxicity occurs. 5.7 Hyperkalemia Hyperkalemia has been reported with tacrolimus use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during tacrolimus therapy [see Adverse Reactions (6.1) ] . Monitor serum potassium levels periodically during treatment. 5.8 Hypertension Hypertension is a common adverse effect of tacrolimus therapy and may require antihypertensive therapy [see Adverse Reactions (6.1) ] . The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions (5.7) ] . Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [see Drug Interactions (7.2) ]. 5.9 Anaphylactic Reactions with Tacrolimus Injection Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus injection, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take tacrolimus orally. Monitor patients for anaphylaxis when using the intravenous route of administration [see]. 5.10 Not Recommended for Use with Sirolimus Tacrolimus is not recommended for use with sirolimus: The use of sirolimus with tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT), and is not recommended. The use of sirolimus (2 mg per day) with tacrolimus in heart transplant patients in a U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies (14.3) ] . The use of sirolimus with tacrolimus may increase the risk of thrombotic microangiopathy [see Warnings and Precautions (5.16) ] . 5.11 Interactions with CYP3A4 Inhibitors and Inducers When co-administering tacrolimus with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions (7.2) ] . 5.12 QT Prolongation Tacrolimus may prolong the QT/QTc interval and may cause Torsade de Pointes . Avoid tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.
king certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. When co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of tacrolimus with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions (7.2) ] . 5.13 Myocardial Hypertrophy Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered [see Adverse Reactions (6.2) ] . 5.14 Immunizations Whenever possible, administer the complete complement of vaccines before transplantation and treatment with tacrolimus. The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: 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 tacrolimus. 5.15 Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of tacrolimus should be considered [see Adverse Reactions (6.2) ] . 5.16 Thrombotic Microangiopathy (Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura) Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with tacrolimus. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA. In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA. 5.17 Cannabidiol Drug Interactions 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 Drug Interactions (7.3) ] .
6 ADVERSE REACTIONS The following serious and otherwise important 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) ] New Onset Diabetes After Transplant [see Warnings and Precautions (5.4) ] Nephrotoxicity [see Warnings and Precautions (5.5) ] Neurotoxicity [see Warnings and Precautions (5.6) ] Hyperkalemia [see Warnings and Precautions (5.7) ] Hypertension [see Warnings and Precautions (5.8) ] Anaphylactic Reactions with Tacrolimus Injection [see Warnings and Precautions (5.9) ] Myocardial Hypertrophy [see Warnings and Precautions (5.13) ] Pure Red Cell Aplasia [see Warnings and Precautions (5.15) ] Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions (5.16) ] The most common adverse reactions (≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 Transplantation The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression. Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received tacrolimus-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on tacrolimus and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below. The most common adverse reactions (≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below: Table 4.
Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below: Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) Tacrolimus/AZA (N = 205) Cyclosporine/AZA (N = 207) Nervous System Tremor 54% 34% Headache 44% 38% Insomnia 32% 30% Paresthesia 23% 16% Dizziness 19% 16% Gastrointestinal Diarrhea 44% 41% Nausea 38% 36% Constipation 35% 43% Vomiting 29% 23% Dyspepsia 28% 20% Cardiovascular Hypertension 50% 52% Chest Pain 19% 13% Urogenital Creatinine Increased 45% 42% Urinary Tract Infection 34% 35% Metabolic and Nutritional Hypophosphatemia 49% 53% Hypomagnesemia 34% 17% Hyperlipemia 31% 38% Hyperkalemia 31% 32% Diabetes Mellitus 24% 9% Hypokalemia 22% 25% Hyperglycemia 22% 16% Edema 18% 19% Hemic and Lymphatic Anemia 30% 24% Leukopenia 15% 17% Miscellaneous Infection 45% 49% Peripheral Edema 36% 48% Asthenia 34% 30% Abdominal Pain 33% 31% Pain 32% 30% Fever 29% 29% Back Pain 24% 20% Respiratory System Dyspnea 22% 18% Cough Increased 18% 15% Musculoskeletal Arthralgia 25% 24% Skin Rash 17% 12% Pruritus 15% 7% Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-U.S. trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n = 403), or one of two cyclosporine (CsA) regimens (Group A, n = 384 and Group B, n = 408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below: Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1) Tacrolimus (Group C) (N = 403) Cyclosporine (Group A) (N = 384) Cyclosporine (Group B) (N = 408) Diarrhea 25% 16% 13% Urinary Tract Infection 24% 28% 24% Anemia 17% 19% 17% Hypertension 13% 14% 12% Leukopenia 13% 10% 10% Edema Peripheral 11% 12% 13% Hyperlipidemia 10% 15% 13% Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n = 212) or cyclosporine (n = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below: Table 6.
he composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below: Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2) Tacrolimus/MMF (N = 212) Cyclosporine/MMF (N = 212) Gastrointestinal Disorders Diarrhea 44% 26% Nausea 39% 47% Constipation 36% 41% Vomiting 26% 25% Dyspepsia 18% 15% Injury, Poisoning, and Procedural Complications Post-Procedural Pain 29% 27% Incision Site Complication 28% 23% Graft Dysfunction 24% 18% Metabolism and Nutrition Disorders Hypomagnesemia 28% 22% Hypophosphatemia 28% 21% Hyperkalemia 26% 19% Hyperglycemia 21% 15% Hyperlipidemia 18% 25% Hypokalemia 16% 18% Nervous System Disorders Tremor 34% 20% Headache 24% 25% Blood and Lymphatic System Disorders Anemia 30% 28% Leukopenia 16% 12% Miscellaneous Edema Peripheral 35% 46% Hypertension 32% 35% Insomnia 30% 21% Urinary Tract Infection 26% 22% Blood Creatinine Increased 23% 23% Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.” Liver Transplantation There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70); the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%), and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%), and Other (2%). The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥ 15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation. The most common adverse reactions (≥ 40%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials. Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus U.S.
se reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials. Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus U.S. TRIAL EUROPEAN TRIAL Tacrolimus (N = 250) Cyclosporine/AZA (N = 250) Tacrolimus (N = 264) Cyclosporine/AZA (N = 265) Nervous System Headache 64% 60% 37% 26% Insomnia 64% 68% 32% 23% Tremor 56% 46% 48% 32% Paresthesia 40% 30% 17% 17% Gastrointestinal Diarrhea 72% 47% 37% 27% Nausea 46% 37% 32% 27% LFT Abnormal 36% 30% 6% 5% Anorexia 34% 24% 7% 5% Vomiting 27% 15% 14% 11% Constipation 24% 27% 23% 21% Cardiovascular Hypertension 47% 56% 38% 43% Urogenital Kidney Function Abnormal 40% 27% 36% 23% Creatinine Increased 39% 25% 24% 19% BUN Increased 30% 22% 12% 9% Oliguria 18% 15% 19% 12% Urinary Tract Infection 16% 18% 21% 19% Metabolic and Nutritional Hypomagnesemia 48% 45% 16% 9% Hyperglycemia 47% 38% 33% 22% Hyperkalemia 45% 26% 13% 9% Hypokalemia 29% 34% 13% 16% Hemic and Lymphatic Anemia 47% 38% 5% 1% Leukocytosis 32% 26% 8% 8% Thrombocytopenia 24% 20% 14% 19% Miscellaneous Pain 63% 57% 24% 22% Abdominal Pain 59% 54% 29% 22% Asthenia 52% 48% 11% 7% Fever 48% 56% 19% 22% Back Pain 30% 29% 17% 17% Ascites 27% 22% 7% 8% Peripheral Edema 26% 26% 12% 14% Respiratory System Pleural Effusion 30% 32% 36% 35% Dyspnea 29% 23% 5% 4% Atelectasis 28% 30% 5% 4% Skin and Appendages Pruritus 36% 20% 15% 7% Rash 24% 19% 10% 4% Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.” Heart Transplantation The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with tacrolimus (n = 157) or cyclosporine (n = 157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%). The most common adverse reactions (≥ 15%) observed in tacrolimus-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial. Adverse reactions in heart transplant patients in the European trial are presented below: Table 8.
ry tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial. Adverse reactions in heart transplant patients in the European trial are presented below: Table 8. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) Tacrolimus/AZA (N = 157) Cyclosporine/AZA (N = 157) Cardiovascular System Hypertension 62% 69% Pericardial Effusion 15% 14% Body as a Whole CMV Infection 32% 30% Infection 24% 21% Metabolic and Nutritional Disorders Diabetes Mellitus 26% 16% Hyperglycemia 23% 17% Hyperlipemia 18% 27% Hemic and Lymphatic System Anemia 50% 36% Leukopenia 48% 39% Urogenital System Kidney Function Abnormal 56% 57% Urinary Tract Infection 16% 12% Respiratory System Bronchitis 17% 18% Nervous System Tremor 15% 6% In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and tacrolimus in combination with sirolimus (n = 109), tacrolimus in combination with MMF (n = 107) or cyclosporine modified in combination with MMF (n = 115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%). Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with tacrolimus and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%) , hypertriglyceridemia (65%), anemia (hemoglobin < 10.0 g/dL) (65%), fasting blood glucose > 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs < 3000 cells/mcL (34%), serious bacterial infections (30%), magnesium < 1.2 mEq/L (24%), platelet count < 75,000 cells/mcL (19%), and other opportunistic infections (15%). Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.” New Onset Diabetes After Transplant Kidney Transplantation New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥ 126 mg/dL, HbA 1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the NEORAL ® -treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies (14.1) ] . Table 9.
mg/dL, HbA 1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the NEORAL ® -treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies (14.1) ] . Table 9. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2) Parameter Treatment Group Tacrolimus/MMF (N = 212) NEORAL/MMF (N = 212) NODAT 112/150 (75%) 93/152 (61%) Fasting Plasma Glucose ≥ 126 mg/dL 96/150 (64%) 80/152 (53%) HbA 1c ≥ 6% 59/150 (39%) 28/152 (18%) Insulin Use ≥ 30 days 9/150 (6%) 4/152 (3%) Oral Hypoglycemic Use 15/150 (10%) 5/152 (3%) In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of “use of insulin for 30 or more consecutive days with < 5-day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14. PTDM was reported in 20% of tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 11). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12). Table 10. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA) Status of PTDM Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Tacrolimus/AZA CsA/AZA Patients without pre-transplant history of diabetes mellitus 151 151 New onset PTDM , 1 st Year 30/151 (20%) 6/151 (4%) Still insulin-dependent at one year in those without prior history of diabetes 25/151 (17%) 5/151 (3%) New onset PTDM post 1 year 1 0 Patients with PTDM at 2 years 16/151 (11%) 5/151 (3%) Table 11. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial Patient Race Patients Who Developed PTDM Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Tacrolimus Cyclosporine African-American 15/41 (37%) 3 (8%) Hispanic 5/17 (29%) 1 (6%) Caucasian 10/82 (12%) 1 (1%) Other 0/11 (0%) 1 (10%) Total 30/151 (20%) 6 (4%) Liver Transplantation Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively (Table 13). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1) ]. Table 12. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients Status of PTDM Patients without pre-transplant history of diabetes mellitus. U.S. Trial European Trial Tacrolimus Cyclosporine Tacrolimus Cyclosporine Patients at risk Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
nts without pre-transplant history of diabetes mellitus. U.S. Trial European Trial Tacrolimus Cyclosporine Tacrolimus Cyclosporine Patients at risk Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. 239 236 239 249 New Onset PTDM 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) Heart Transplantation Insulin-dependent PTDM was reported in 13% and 22% of tacrolimus-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 14). Hyperglycemia, defined as two fasting plasma glucose levels ≥ 126 mg/dL, was reported with the use of tacrolimus plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1) ]. Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients Status of PTDM Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. U.S. Trial European Trial Tacrolimus/ MMF Cyclosporine/ MMF Tacrolimus/ AZA Cyclosporine/ AZA Patients at risk Patients without pre-transplant history of diabetes mellitus. 75 83 132 138 New Onset PTDM 10 (13%) 6 (7%) 29 (22%) 5 (4%) Patients still on insulin at 1 year 7-12 months for the U.S. trial. 7 (9%) 1 (1%) 24 (18%) 4 (3%) Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies: The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.
ths for the U.S. trial. 7 (9%) 1 (1%) 24 (18%) 4 (3%) Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies: The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials. Nervous System: Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired Special Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitus Gastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation Urogenital: Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis Metabolic/Nutritional: Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gain Endocrine: Cushing’s syndrome Hemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration Skin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweating Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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.
ing Experience The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug. Other reactions include: Cardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsade de Pointes , venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia, thrombotic microangiopathy Infections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; polyoma virus-associated nephropathy (PVAN) including graft loss Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased Miscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) Nervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope Respiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis Special Senses: Blindness, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome
<table ID="_RefID0EABBG" width="100%"><caption>Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/AZA</content> <content styleCode="bold">(N = 205)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N = 207)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Tremor</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>54%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>44%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Paresthesia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dizziness</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>44%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>41%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>43%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragra
paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>43%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragra ph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspepsia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>50%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>52%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Chest Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Creatinine Increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Urinary Tract Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypophosphatemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>49%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>53%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypomagnesemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperlipemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperkalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td>
ragraph>38%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperkalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td> </tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diabetes Mellitus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypokalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperglycemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Edema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Miscellaneous</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>49%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Peripheral Edema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Asthenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Abdominal Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>33%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><
Rrule Lrule Botrule " valign="top"><paragraph>33%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top">< paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fever</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Back Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Cough Increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Arthralgia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rash</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7%</paragraph></td></tr></tbody></table>
agraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7%</paragraph></td></tr></tbody></table> <table ID="_RefID0ECXBG" width="100%"><caption>Table 5.
agraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7%</paragraph></td></tr></tbody></table> <table ID="_RefID0ECXBG" width="100%"><caption>Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)</caption><col width="28%"/><col width="23%"/><col width="23%"/><col width="26%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus</content></paragraph><paragraph><content styleCode="bold">(Group C)</content></paragraph><paragraph><content styleCode="bold">(N = 403)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine</content> <content styleCode="bold">(Group A)</content></paragraph><paragraph><content styleCode="bold">(N = 384)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine</content> <content styleCode="bold">(Group B)</content></paragraph><paragraph><content styleCode="bold">(N = 408)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Urinary Tract Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Edema Peripheral</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hyperli
rule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hyperli pidemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil </paragraph></td></tr></tbody></table> <table ID="_RefID0EQ4BG" width="100%"><caption>Table 6.
pidemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil </paragraph></td></tr></tbody></table> <table ID="_RefID0EQ4BG" width="100%"><caption>Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/MMF</content> <content styleCode="bold">(N = 212)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/MMF</content> <content styleCode="bold">(N = 212)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>44%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>39%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>41%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspepsia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Injury, Poisoning, and Procedural Complications</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Post-Procedural Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Incision Site Complication</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Graft Dysfunction</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td
graph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Graft Dysfunction</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypomagnesemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypophosphatemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperkalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperglycemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperlipidemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypokalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Tremor</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Blood and Lymphatic System Disorders</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><
aragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td>< td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Miscellaneous</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Edema Peripheral</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>46%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Urinary Tract Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Blood Creatinine Increased</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>23%</paragraph></td></tr></tbody></table>
r><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Blood Creatinine Increased</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>23%</paragraph></td></tr></tbody></table> <table ID="_RefID0EUMAI" width="100%"><caption>Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus</caption><col width="26%"/><col width="15%"/><col width="22%"/><col width="15%"/><col width="22%"/><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">U.S.
Patients Treated with Tacrolimus</caption><col width="26%"/><col width="15%"/><col width="22%"/><col width="15%"/><col width="22%"/><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">U.S. TRIAL</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">EUROPEAN TRIAL</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus</content> <content styleCode="bold">(N = 250)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N = 250)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus</content></paragraph><paragraph><content styleCode="bold">(N = 264)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N = 265)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>64%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>64%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>68%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Tremor</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>46%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Paresthesia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td sty
le Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td sty leCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>72%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>46%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> LFT Abnormal</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anorexia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56%</paragraph>
e="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56%</paragraph> </td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>43%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Kidney Function Abnormal</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Creatinine Increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>39%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> BUN Increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Oliguria</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Urinary Tract Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypomagnesemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center
paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center " styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperglycemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>33%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperkalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypokalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukocytosis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Thrombocytopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Miscellaneous</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pain</pa
"><paragraph><content styleCode="bold">Miscellaneous</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pain</pa ragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>63%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>57%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Abdominal Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>59%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>54%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Asthenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>52%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fever</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Back Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Ascites</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Peripheral Edema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><t
aph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><t d styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pleural Effusion</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Atelectasis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and Appendages</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Rash</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table>
agraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table> <table ID="_RefID0E4PBI" width="100%"><caption>Table 8.
agraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table> <table ID="_RefID0E4PBI" width="100%"><caption>Table 8. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)</caption><col width="50%"/><col width="24%"/><col width="26%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/AZA</content> <content styleCode="bold">(N = 157)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N = 157)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular System</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>62%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>69%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pericardial Effusion</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> CMV Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diabetes Mellitus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperglycemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperlipemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and
Hyperlipemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic System</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>50%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>39%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital System</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Kidney Function Abnormal</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>57%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Urinary Tract Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Bronchitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Tremor</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6%</paragraph></td></tr></tbody></table>
valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Tremor</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6%</paragraph></td></tr></tbody></table> <table ID="_RefID0EP2BI" width="100%"><caption>Table 9. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Parameter</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Treatment Group</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/MMF</content> <content styleCode="bold">(N = 212)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NEORAL/MMF</content> <content styleCode="bold">(N = 212)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NODAT</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>112/150 (75%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>93/152 (61%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fasting Plasma Glucose ≥ 126 mg/dL</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>96/150 (64%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>80/152 (53%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> HbA <sub>1c</sub>≥ 6% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>59/150 (39%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>28/152 (18%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Insulin Use ≥ 30 days</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>9/150 (6%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>4/152 (3%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Oral Hypoglycemic Use</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>15/150 (10%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>5/152 (3%)</paragraph></td></tr></tbody></table>
Rrule Botrule Lrule " valign="top"><paragraph> Oral Hypoglycemic Use</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>15/150 (10%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>5/152 (3%)</paragraph></td></tr></tbody></table> <table ID="_RefID0EN6BI" width="100%"><caption>Table 10. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)</caption><col width="50%"/><col width="25%"/><col width="25%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Status of PTDM</content><footnote ID="_Ref523387255">Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/AZA</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">CsA/AZA</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Patients without pre-transplant history of diabetes mellitus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>151</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>151</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>New onset PTDM <footnoteRef IDREF="_Ref523387255"/>, 1 <sup>st</sup>Year </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>30/151 (20%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>6/151 (4%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Still insulin-dependent at one year in those without prior history of diabetes</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>25/151 (17%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>5/151 (3%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>New onset PTDM <footnoteRef IDREF="_Ref523387255"/>post 1 year </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Patients with PTDM <footnoteRef IDREF="_Ref523387255"/>at 2 years </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>16/151 (11%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>5/151 (3%)</paragraph></td></tr></tbody></table>
h>Patients with PTDM <footnoteRef IDREF="_Ref523387255"/>at 2 years </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>16/151 (11%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>5/151 (3%)</paragraph></td></tr></tbody></table> <table ID="_RefID0EIDCI" width="100%"><caption>Table 11. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Patient Race</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Patients Who Developed PTDM</content><footnote ID="_Ref523387318">Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</footnote></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>African-American</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15/41 (37%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (8%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hispanic</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5/17 (29%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (6%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Caucasian</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10/82 (12%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Other</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0/11 (0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (10%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Total</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>30/151 (20%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6 (4%)</paragraph></td></tr></tbody></table>
td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Total</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>30/151 (20%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6 (4%)</paragraph></td></tr></tbody></table> <table ID="_RefID0E5HCI" width="100%"><caption>Table 12. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients</caption><col width="21%"/><col width="21%"/><col width="21%"/><col width="21%"/><col width="17%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Status of PTDM</content><footnote ID="_Ref523387463">Patients without pre-transplant history of diabetes mellitus. </footnote></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">U.S. Trial</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">European Trial</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Patients at risk <footnote ID="_Ref523387456">Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>239</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>236</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>239</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>249</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>New Onset PTDM <footnoteRef IDREF="_Ref523387463"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>42 (18%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>30 (13%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>26 (11%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>12 (5%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Patients still on insulin at 1 year</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>23 (10%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>19 (8%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>18 (8%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>6 (2%)</paragraph></td></tr></tbody></table>
="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>19 (8%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>18 (8%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>6 (2%)</paragraph></td></tr></tbody></table> <table ID="_RefID0ETNCI" width="100%"><caption>Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients</caption><col width="21%"/><col width="21%"/><col width="21%"/><col width="21%"/><col width="17%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Status of PTDM</content><footnote ID="_Ref523387537">Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. </footnote></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">U.S. Trial</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">European Trial</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/</content> <content styleCode="bold">MMF</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/</content> <content styleCode="bold">MMF</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/</content> <content styleCode="bold">AZA</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/</content> <content styleCode="bold">AZA</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Patients at risk <footnote ID="_Ref523387550">Patients without pre-transplant history of diabetes mellitus.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>75</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>83</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>132</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>138</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>New Onset PTDM <footnoteRef IDREF="_Ref523387537"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>10 (13%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>6 (7%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>29 (22%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>5 (4%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Patients still on insulin at 1 year <footnote ID="_Ref523387577">7-12 months for the U.S. trial.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>7 (9%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>1 (1%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>24 (18%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>4 (3%)</paragraph></td></tr></tbody></table>
7 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 14: Effects of Other Drugs/Substances on Tacrolimus 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. 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 (5.6 , 5.11 , 5.12) ] . Avoid grapefruit or grapefruit juice. 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 (5.11) ] . 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 : 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) ] .
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 capsules 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) ] .
<table ID="_RefID0EY2CI" width="100%"><caption>Table 14: Effects of Other Drugs/Substances on Tacrolimus <footnote ID="_Ref523387862">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. </footnote></caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Drug/Substance Class or Name</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Drug Interaction Effect</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Recommendations</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Grapefruit or grapefruit juice <footnote ID="_Ref523387870">High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor. </footnote></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see <linkHtml href="#ID_003d91fe-5ff6-462b-acc5-5f6ae2467a09">Warnings and Precautions (5.6</linkHtml>, <linkHtml href="#ID_fce90190-926b-43a8-92af-078384149f0d">5.11</linkHtml>, <linkHtml href="#ID_f6444aa1-926b-410d-8309-392b04b7ef2e">5.12)</linkHtml>] </content>. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Avoid grapefruit or grapefruit juice.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Strong CYP3A Inducers <footnote ID="_Ref523387879">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). </footnote>: </paragraph><paragraph> Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s wort</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection <content styleCode="italics">[see <linkHtml href="#ID_fce90190-926b-43a8-92af-078384149f0d">Warnings and Precautions (5.11)</linkHtml>] </content>. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations <content styleCode="italics">[see <linkHtml href="#ID_ede14e0a-13be-4304-a660-f54d207d77a6">Dosage and Administration (2.2</linkHtml>, <linkHtml href="#ID_ea5b6dcd-72a2-4a57-9dfa-8691ff790d7b">2.6)</linkHtml>and <linkHtml href="#ID_74a449dd-60f8-46d3-9c8c-57e605203137">Clinical Pharmacology (12.3)</linkHtml>] </content>.
ontent styleCode="italics">[see <linkHtml href="#ID_ede14e0a-13be-4304-a660-f54d207d77a6">Dosage and Administration (2.2</linkHtml>, <linkHtml href="#ID_ea5b6dcd-72a2-4a57-9dfa-8691ff790d7b">2.6)</linkHtml>and <linkHtml href="#ID_74a449dd-60f8-46d3-9c8c-57e605203137">Clinical Pharmacology (12.3)</linkHtml>] </content>. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Strong CYP3A Inhibitors <footnoteRef IDREF="_Ref523387879"/>: </paragraph><paragraph> Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, <content styleCode="italics">Schisandra sphenanthera</content>extracts </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>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 <content styleCode="italics">[see <linkHtml href="#ID_003d91fe-5ff6-462b-acc5-5f6ae2467a09">Warnings and Precautions (5.6</linkHtml>, <linkHtml href="#ID_fce90190-926b-43a8-92af-078384149f0d">5.11</linkHtml>, <linkHtml href="#ID_f6444aa1-926b-410d-8309-392b04b7ef2e">5.12)</linkHtml>] </content>. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Reduce tacrolimus dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations <content styleCode="italics">[see <linkHtml href="#ID_ede14e0a-13be-4304-a660-f54d207d77a6">Dosage and Administration (2.2</linkHtml>, <linkHtml href="#ID_ea5b6dcd-72a2-4a57-9dfa-8691ff790d7b">2.6)</linkHtml>and <linkHtml href="#ID_74a449dd-60f8-46d3-9c8c-57e605203137">Clinical Pharmacology (12.3)</linkHtml>] </content>. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary <content styleCode="italics">[see <linkHtml href="#ID_fce90190-926b-43a8-92af-078384149f0d">Warnings and Precautions (5.11)</linkHtml>] </content>. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mild or Moderate CYP3A Inhibitors:</paragraph><paragraph> Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see <linkHtml href="#ID_003d91fe-5ff6-462b-acc5-5f6ae2467a09">Warnings and Precautions (5.6</linkHtml>, <linkHtml href="#ID_fce90190-926b-43a8-92af-078384149f0d">5.11</linkHtml>, <linkHtml href="#ID_f6444aa1-926b-410d-8309-392b04b7ef2e">5.12)</linkHtml>] </content>. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed <content styleCode="italics">[see <linkHtml href="#ID_ede14e0a-13be-4304-a660-f54d207d77a6">Dosage and Administration (2.2</linkHtml>, <linkHtml href="#ID_ea5b6dcd-72a2-4a57-9dfa-8691ff790d7b">2.6)</linkHtml>and <linkHtml href="#ID_74a449dd-60f8-46d3-9c8c-57e605203137">Clinical Pharmacology (12.3)</linkHtml>] </content>.
ontent styleCode="italics">[see <linkHtml href="#ID_ede14e0a-13be-4304-a660-f54d207d77a6">Dosage and Administration (2.2</linkHtml>, <linkHtml href="#ID_ea5b6dcd-72a2-4a57-9dfa-8691ff790d7b">2.6)</linkHtml>and <linkHtml href="#ID_74a449dd-60f8-46d3-9c8c-57e605203137">Clinical Pharmacology (12.3)</linkHtml>] </content>. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Other drugs, such as:</paragraph><paragraph> Magnesium and aluminum hydroxide antacids</paragraph><paragraph> Metoclopramide</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see <linkHtml href="#ID_003d91fe-5ff6-462b-acc5-5f6ae2467a09">Warnings and Precautions (5.6</linkHtml>, <linkHtml href="#ID_fce90190-926b-43a8-92af-078384149f0d">5.11</linkHtml>, <linkHtml href="#ID_f6444aa1-926b-410d-8309-392b04b7ef2e">5.12)</linkHtml>] </content>. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed <content styleCode="italics">[see <linkHtml href="#ID_ede14e0a-13be-4304-a660-f54d207d77a6">Dosage and Administration (2.2</linkHtml>, <linkHtml href="#ID_ea5b6dcd-72a2-4a57-9dfa-8691ff790d7b">2.6)</linkHtml>and <linkHtml href="#ID_74a449dd-60f8-46d3-9c8c-57e605203137">Clinical Pharmacology (12.3)</linkHtml>] </content>. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>Mild or Moderate CYP3A Inducers</paragraph><paragraph> Methylprednisolone, prednisone</paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>May decrease tacrolimus whole blood trough concentrations.</paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed <content styleCode="italics">[see <linkHtml href="#ID_ede14e0a-13be-4304-a660-f54d207d77a6">Dosage and Administration (2.2</linkHtml>, <linkHtml href="#ID_ea5b6dcd-72a2-4a57-9dfa-8691ff790d7b">2.6)</linkHtml>] </content>. </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Caspofungin</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>May decrease tacrolimus whole blood trough concentrations.</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed <content styleCode="italics">[see <linkHtml href="#ID_ede14e0a-13be-4304-a660-f54d207d77a6">Dosage and Administration (2.2</linkHtml>, <linkHtml href="#ID_ea5b6dcd-72a2-4a57-9dfa-8691ff790d7b">2.6)</linkHtml>] </content>. </paragraph></td></tr></tbody></table>
8 USE IN SPECIFIC POPULATIONS Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. ( 8.1 , 8.3 ) Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to tacrolimus 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data ] . The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death. Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population.
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 Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions (5.4) ] . Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions (5.7 , 5.8) ]. 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 tacrolimus. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus. 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 16. 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 renal 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 15. 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 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed.
kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), 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 to 6.9 times the recommended clinical dose range) 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 to 6.9 times the recommended clinical dose range); 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 to 2.2 times the recommended clinical dose range). 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 to 6.9 times the 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 to 2.2 times the recommended clinical dose range) [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 Use in Specific Populations (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 tacrolimus and any potential adverse effects on the breastfed child from tacrolimus or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Tacrolimus 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 tacrolimus [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 tacrolimus [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use Safety and effectiveness have been established in pediatric liver, kidney and heart transplant patients. Liver Transplantation Safety and efficacy in pediatric liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus, and supported by two pharmacokinetic and safety studies in 151 children who received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations.
by two pharmacokinetic and safety studies in 151 children who received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients [see, Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.2) ] . Kidney and Heart Transplantation Use of tacrolimus capsules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 8.5 Geriatric Use Clinical trials of tacrolimus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 volunteers with normal renal function. However, consideration should be given to dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration (2.4) 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 volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology (12.3) ] . The use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. 8.8 Race or Ethnicity African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] . 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 (5.4) ] .
<table ID="_RefID0E4NDI" width="100%"><caption>Table 15. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Kidney</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Liver</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Pregnancy Outcomes</content><footnote ID="_Ref523388012">Includes multiple births and terminations. </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">462</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">253</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold"> Miscarriage</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24.5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold"> Live births</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">331</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">180</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pre-term delivery (< 37 weeks)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>49%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Low birth weight (< 2500 g)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Birth defects</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>8% <footnote ID="_Ref523388025">Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>5%</paragraph></td></tr></tbody></table>
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to tacrolimus 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data ] . The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death. Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported. Maternal Adverse Reactions Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions (5.4) ] . Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia.
g were reported. Maternal Adverse Reactions Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions (5.4) ] . Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions (5.7 , 5.8) ]. 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 tacrolimus. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus. 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 16. 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 renal 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 15. 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 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), 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 to 6.9 times the recommended clinical dose range) 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.
o 6.9 times the recommended clinical dose range) 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 to 6.9 times the recommended clinical dose range); 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 to 2.2 times the recommended clinical dose range). 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 to 6.9 times the 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 to 2.2 times the recommended clinical dose range) [see Nonclinical Toxicology (13.1) ] .
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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data ] . The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
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. 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 Use in Specific Populations (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 tacrolimus and any potential adverse effects on the breastfed child from tacrolimus or from the underlying maternal condition.
8.4 Pediatric Use Safety and effectiveness have been established in pediatric liver, kidney and heart transplant patients. Liver Transplantation Safety and efficacy in pediatric liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus, and supported by two pharmacokinetic and safety studies in 151 children who received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients [see, Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.2) ] . Kidney and Heart Transplantation Use of tacrolimus capsules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
8.5 Geriatric Use Clinical trials of tacrolimus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.
10 OVERDOSAGE Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of tacrolimus [see Adverse Reactions (6.1 , 6.2) ], including tremors, abnormal renal function, hypertension, and peripheral edema; in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
11 DESCRIPTION Tacrolimus, previously known as FK506, is the active ingredient in tacrolimus capsules. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as (‒)-(3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-8-Allyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylvinyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone monohydrate. The chemical structure of tacrolimus is: Tacrolimus has a molecular formula of C 44 H 69 NO 12 •H 2 O and a formula weight of 822.03. Tacrolimus, USP appears as a white to off-white powder. It is insoluble in water, very soluble in ethanol, and soluble in methanol and chloroform. Tacrolimus capsules, USP are available for oral administration as capsules containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. Inactive ingredients include anhydrous lactose, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. The 0.5 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules also contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules also contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10. In addition, the black imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze. Meets USP Dissolution Test 5. Tacrolimus Structural Formula
12 CLINICAL PHARMACOLOGY 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, 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 16. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients Population N Route (Dose) Parameters C max (ng/mL) T max (hr) AUC (ng•hr/mL) t 1/2 (hr) CL (L/hr/kg) V (L/kg) Healthy Volunteers 8 IV (0.025 mg/kg/4hr) Not applicable 652 AUC 0-inf ± 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 Not available IV (0.02 mg/kg/12 hr) 294 ± 262 18.8 ± 16.7 0.083 ± 0.050 1.41 ± 0.66 Kidney Transplant Patients 26 PO (0.2 mg/kg/day) 19.2 ± 10.3 3.0 203 ± 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 ± 30.0 2.3 ± 1.5 519 ± 179 11 IV (0.01 mg/kg/day as a continuous infusion) 954 AUC 0-t ± 334 23.6 ± 9.22 0.051 ± 0.015 Heart Transplant Patients 11 PO (0.075 mg/kg/day) Determined after the first dose 14.7 ± 7.79 2.1 [0.5-6.0] Median [range] 82.7 AUC 0-12 ± 63.2 14 PO (0.15 mg/kg/day) 24.5 ± 13.7 1.5 [0.4-4.0] 142 ± 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.
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 (C max ) 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 10-12 hours post-dose (C min ) 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. In a healthy volunteer adult study, the systemic exposure to tacrolimus (AUC) for tacrolimus for oral suspension was approximately 16% higher than that for tacrolimus capsules when administered as single doses. 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 C max were decreased 37% and 77%, respectively; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max 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 C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C max 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 C max (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 5-50 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 (CYP3A 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.
em (CYP3A 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 ± 1.0% 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 Pediatric Patients Tacrolimus Capsules Pharmacokinetics in Pediatric Patients Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C max were 337 ± 167 ng•hr/mL and 48.4 ± 27.9 ng/mL, respectively. The absolute bioavailability was 31 ± 24%. Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2 ± 2.4 years of age. Following IV infusion of a 0.06 mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2 ± 5.0 hours and 0.12 ± 0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and C max were 181 ± 65 ng•hr/mL and 30 ± 11 ng/mL, respectively. The absolute bioavailability was 19 ± 14%. Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration (2.3) ]. Renal and Hepatic Impairment Patients The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19. Table 17. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients Population (No.
Dosage and Administration (2.3) ]. Renal and Hepatic Impairment Patients The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19. Table 17. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients Population (No. of Patients) Dose AUC 0-t (ng•hr/mL) t 1/2 (hr) V (L/kg) CL (L/hr/kg) Renal Impairment (n = 12) 0.02 mg/kg/4 hr IV 393 ± 123 (t = 60 hr) 26.3 ± 9.2 1.07 ± 0.20 0.038 ± 0.014 Mild Hepatic Impairment (n = 6) 0.02 mg/kg/4 hr IV 367 ± 107 (t = 72 hr) 60.6 ± 43.8 Range: 27.8 ˗ 141 3.1 ± 1.6 0.042 ± 0.02 7.7 mg PO 488 ± 320 (t = 72 hr) 66.1 ± 44.8 Range: 29.5˗138 3.7 ± 4.7 Corrected for bioavailability 0.034 ± 0.019 Severe Hepatic Impairment (n = 6, IV) 0.02 mg/kg/4 hr IV (n = 2) 762 ± 204 (t = 120 hr) 198 ± 158 Range:81 ˗ 436 3.9 ± 1.0 0.017 ± 0.013 0.01 mg/kg/8 hr IV (n = 4) 289 ± 117 (t = 144 hr) (n = 5, PO) 1 patient did not receive the PO dose 8 mg PO (n = 1) 658 (t = 120 hr) 119 ± 35 Range: 85 ˗ 178 3.1 ± 3.4 0.016 ± 0.011 5 mg PO (n = 4) 533 ± 156 (t = 144 hr) 4 mg PO (n = 1) Patients with Renal Impairment Tacrolimus pharmacokinetics, following a single IV administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 19) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration (2.5) and Use in Specific Populations (8.7) ] . Patients with Cystic Fibrosis Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration (2.2 , 2.3) ] . Racial or Ethnic Groups The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of tacrolimus to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (± SD) tacrolimus C max in African-Americans (23.6 ± 12.1 ng/mL) was significantly lower than in Caucasians (40.2 ± 12.6 ng/mL) and the Latino-Americans (36.2 ± 15.8 ng/mL) (p < 0.01). Mean AUC 0-inf tended to be lower in African-Americans (203 ± 115 ng•hr/mL) than Caucasians (344 ± 186 ng•hr/mL) and Latino-Americans (274 ± 150 ng•hr/mL). The mean (± SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was significantly lower than in Caucasians (19 ± 5.8%, p = 0.011). There was no significant difference in mean terminal T 1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration (2.2) ].
T 1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration (2.2) ]. Male and Female Patients A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences. 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 and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus C max relative to tacrolimus administration alone [see Drug Interactions (7.2) ]. Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 ± 5% vs. 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 ± 0.129 L/hr/kg vs. 0.148 ± 0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions (7.2) ] . Voriconazole (see complete prescribing information for VFEND ® ): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUC τ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7.2) ] .
eat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUC τ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7.2) ] . Posaconazole (see complete prescribing information for Noxafil ® ): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) C max and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions (7.2) ] . Caspofungin (see complete prescribing information for CANCIDAS ® ): Caspofungin reduced the blood AUC 0-12 of tacrolimus by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C 12hr ) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions (7.2) ] . The mechanism of interaction has not been confirmed.
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 16. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients Population N Route (Dose) Parameters C max (ng/mL) T max (hr) AUC (ng•hr/mL) t 1/2 (hr) CL (L/hr/kg) V (L/kg) Healthy Volunteers 8 IV (0.025 mg/kg/4hr) Not applicable 652 AUC 0-inf ± 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 Not available IV (0.02 mg/kg/12 hr) 294 ± 262 18.8 ± 16.7 0.083 ± 0.050 1.41 ± 0.66 Kidney Transplant Patients 26 PO (0.2 mg/kg/day) 19.2 ± 10.3 3.0 203 ± 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 ± 30.0 2.3 ± 1.5 519 ± 179 11 IV (0.01 mg/kg/day as a continuous infusion) 954 AUC 0-t ± 334 23.6 ± 9.22 0.051 ± 0.015 Heart Transplant Patients 11 PO (0.075 mg/kg/day) Determined after the first dose 14.7 ± 7.79 2.1 [0.5-6.0] Median [range] 82.7 AUC 0-12 ± 63.2 14 PO (0.15 mg/kg/day) 24.5 ± 13.7 1.5 [0.4-4.0] 142 ± 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 (C max ) 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 10-12 hours post-dose (C min ) 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. In a healthy volunteer adult study, the systemic exposure to tacrolimus (AUC) for tacrolimus for oral suspension was approximately 16% higher than that for tacrolimus capsules when administered as single doses. 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.
tacrolimus for oral suspension was approximately 16% higher than that for tacrolimus capsules when administered as single doses. 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 C max were decreased 37% and 77%, respectively; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max 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 C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C max 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 C max (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 5-50 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 (CYP3A 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 ± 1.0% 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%.
nation 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 Pediatric Patients Tacrolimus Capsules Pharmacokinetics in Pediatric Patients Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C max were 337 ± 167 ng•hr/mL and 48.4 ± 27.9 ng/mL, respectively. The absolute bioavailability was 31 ± 24%. Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2 ± 2.4 years of age. Following IV infusion of a 0.06 mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2 ± 5.0 hours and 0.12 ± 0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and C max were 181 ± 65 ng•hr/mL and 30 ± 11 ng/mL, respectively. The absolute bioavailability was 19 ± 14%. Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration (2.3) ]. Renal and Hepatic Impairment Patients The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19. Table 17. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients Population (No. of Patients) Dose AUC 0-t (ng•hr/mL) t 1/2 (hr) V (L/kg) CL (L/hr/kg) Renal Impairment (n = 12) 0.02 mg/kg/4 hr IV 393 ± 123 (t = 60 hr) 26.3 ± 9.2 1.07 ± 0.20 0.038 ± 0.014 Mild Hepatic Impairment (n = 6) 0.02 mg/kg/4 hr IV 367 ± 107 (t = 72 hr) 60.6 ± 43.8 Range: 27.8 ˗ 141 3.1 ± 1.6 0.042 ± 0.02 7.7 mg PO 488 ± 320 (t = 72 hr) 66.1 ± 44.8 Range: 29.5˗138 3.7 ± 4.7 Corrected for bioavailability 0.034 ± 0.019 Severe Hepatic Impairment (n = 6, IV) 0.02 mg/kg/4 hr IV (n = 2) 762 ± 204 (t = 120 hr) 198 ± 158 Range:81 ˗ 436 3.9 ± 1.0 0.017 ± 0.013 0.01 mg/kg/8 hr IV (n = 4) 289 ± 117 (t = 144 hr) (n = 5, PO) 1 patient did not receive the PO dose 8 mg PO (n = 1) 658 (t = 120 hr) 119 ± 35 Range: 85 ˗ 178 3.1 ± 3.4 0.016 ± 0.011 5 mg PO (n = 4) 533 ± 156 (t = 144 hr) 4 mg PO (n = 1) Patients with Renal Impairment Tacrolimus pharmacokinetics, following a single IV administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 19) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations.
ilar to that in normal volunteers (Table 19) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration (2.5) and Use in Specific Populations (8.7) ] . Patients with Cystic Fibrosis Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration (2.2 , 2.3) ] . Racial or Ethnic Groups The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of tacrolimus to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (± SD) tacrolimus C max in African-Americans (23.6 ± 12.1 ng/mL) was significantly lower than in Caucasians (40.2 ± 12.6 ng/mL) and the Latino-Americans (36.2 ± 15.8 ng/mL) (p < 0.01). Mean AUC 0-inf tended to be lower in African-Americans (203 ± 115 ng•hr/mL) than Caucasians (344 ± 186 ng•hr/mL) and Latino-Americans (274 ± 150 ng•hr/mL). The mean (± SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was significantly lower than in Caucasians (19 ± 5.8%, p = 0.011). There was no significant difference in mean terminal T 1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration (2.2) ]. Male and Female Patients A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences. 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) ] .
us 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 and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus C max relative to tacrolimus administration alone [see Drug Interactions (7.2) ]. Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 ± 5% vs. 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 ± 0.129 L/hr/kg vs. 0.148 ± 0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions (7.2) ] . Voriconazole (see complete prescribing information for VFEND ® ): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUC τ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7.2) ] . Posaconazole (see complete prescribing information for Noxafil ® ): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) C max and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions (7.2) ] . Caspofungin (see complete prescribing information for CANCIDAS ® ): Caspofungin reduced the blood AUC 0-12 of tacrolimus by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C 12hr ) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions (7.2) ] . The mechanism of interaction has not been confirmed.
<table ID="_RefID0E5BAK" width="100%"><caption>Table 16. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients</caption><col width="11%"/><col width="10%"/><col width="11%"/><col width="11%"/><col width="11%"/><col width="12%"/><col width="11%"/><col width="11%"/><col width="11%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Population</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Route</content> <content styleCode="bold">(Dose)</content></paragraph></td><td align="center" colspan="6" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Parameters</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">C <sub>max</sub></content> <content styleCode="bold">(ng/mL)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">T <sub>max</sub></content></paragraph><paragraph><content styleCode="bold">(hr)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">AUC</content> <content styleCode="bold">(ng•hr/mL)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">t <sub>1/2</sub></content> <content styleCode="bold">(hr)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">CL</content> <content styleCode="bold">(L/hr/kg)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">V</content> <content styleCode="bold">(L/kg)</content></paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Healthy Volunteers</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>IV (0.025 mg/kg/4hr)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnote ID="_Ref523388210">Not applicable </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388210"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>652 <footnote ID="_Ref523388225">AUC 0-inf</footnote>± 156 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34.2 ± 7.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.040 ± 0.009</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.91 ± 0.31</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (5 mg) (capsules)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28.8 ± 8.9</paragraph></td><td align
n="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (5 mg) (capsules)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28.8 ± 8.9</paragraph></td><td align ="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.5 ± 0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>266 <footnoteRef IDREF="_Ref523388225"/>± 95 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32.3 ± 8.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnote ID="_Ref523388303">Not available </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>IV (0.02 mg/kg/12 hr)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388210"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388210"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>294 <footnoteRef IDREF="_Ref523388225"/>± 262 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18.8 ± 16.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.083 ± 0.050</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.41 ± 0.66</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Kidney Transplant Patients</paragraph></td><td align="center" valign="middle"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (0.2 mg/kg/day)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19.2 ± 10.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>203 <footnoteRef IDREF="_Ref523388225"/>± 42 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (0.3 mg/kg/day)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24.2 ± 15.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>288 <footnoteRef IDREF="_Ref523388225"/>± 93 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td></tr><tr><td r
noteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td></tr><tr><td r owspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Liver Transplant Patients</paragraph></td><td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>IV (0.05 mg/kg/12 hr)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388210"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388210"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3300 <footnoteRef IDREF="_Ref523388225"/>± 2130 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11.7 ± 3.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.053 ± 0.017</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.85 ± 0.30</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (0.3 mg/kg/day)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>68.5 ± 30.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.3 ± 1.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>519 <footnoteRef IDREF="_Ref523388225"/>± 179 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>IV (0.01 mg/kg/day as a continuous infusion)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388210"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388210"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>954 <footnote ID="_Ref523388493">AUC 0-t</footnote>± 334 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23.6 ± 9.22</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.051 ± 0.015</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Heart Transplant Patients</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (0.075 mg/kg/day) <footnote ID="_Ref523388410">Determined after the first dose </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14.7 ± 7.79</paragraph></td><td align="center" st
/td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>PO (0.075 mg/kg/day) <footnote ID="_Ref523388410">Determined after the first dose </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14.7 ± 7.79</paragraph></td><td align="center" st yleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.1 [0.5-6.0] <footnote ID="_Ref523388441">Median [range] </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>82.7 <footnote ID="_Ref523388500">AUC 0-12</footnote>± 63.2 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388210"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>PO (0.15 mg/kg/day) <footnoteRef IDREF="_Ref523388410"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>24.5 ± 13.7</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1.5 [0.4-4.0] <footnoteRef IDREF="_Ref523388441"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>142 <footnoteRef IDREF="_Ref523388500"/>± 116 </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388210"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td></tr></tbody></table>
IDREF="_Ref523388210"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><footnoteRef IDREF="_Ref523388303"/></paragraph></td></tr></tbody></table> <table ID="_RefID0EG6AK" width="100%"><caption>Table 17. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients</caption><col width="18%"/><col width="18%"/><col width="18%"/><col width="18%"/><col width="15%"/><col width="15%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Population (No.
17. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients</caption><col width="18%"/><col width="18%"/><col width="18%"/><col width="18%"/><col width="15%"/><col width="15%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Population (No. of Patients)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Dose</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">AUC <sub>0-t</sub></content> <content styleCode="bold">(ng•hr/mL)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">t <sub>1/2</sub></content> <content styleCode="bold">(hr)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">V</content> <content styleCode="bold">(L/kg)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">CL</content> <content styleCode="bold">(L/hr/kg)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Renal Impairment (n = 12)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.02 mg/kg/4 hr IV </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>393 ± 123 (t = 60 hr) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26.3 ± 9.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.07 ± 0.20</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.038 ± 0.014</paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mild Hepatic Impairment (n = 6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.02 mg/kg/4 hr IV </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>367 ± 107 (t = 72 hr) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60.6 ± 43.8 Range: 27.8 ˗ 141 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.1 ± 1.6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.042 ± 0.02</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.7 mg PO</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>488 ± 320 (t = 72 hr) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>66.1 ± 44.8 Range: 29.5˗138 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.7 ± 4.7 <footnote ID="_Ref523389190">Corrected for bioavailability</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.034 ± 0.019 <footnoteRef IDREF="_Ref523389190"/></paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Severe Hepatic Impairment (n = 6, IV)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>0.02 mg/kg/4 hr IV (n = 2) </paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>762 ± 204 (t = 120 hr) </paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>198 ± 158 Range:81 ˗ 436 </paragraph><
leCode="Rrule Lrule " valign="top"><paragraph>0.02 mg/kg/4 hr IV (n = 2) </paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>762 ± 204 (t = 120 hr) </paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>198 ± 158 Range:81 ˗ 436 </paragraph>< /td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3.9 ± 1.0</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>0.017 ± 0.013</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.01 mg/kg/8 hr IV (n = 4) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>289 ± 117 (t = 144 hr) </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>(n = 5, PO) <footnote ID="_Ref523389165">1 patient did not receive the PO dose </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>8 mg PO (n = 1) </paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>658 (t = 120 hr) </paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>119 ± 35 Range: 85 ˗ 178 </paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3.1 ± 3.4 <footnoteRef IDREF="_Ref523389190"/></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>0.016 ± 0.011 <footnoteRef IDREF="_Ref523389190"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>5 mg PO (n = 4) </paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>533 ± 156 (t = 144 hr) </paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4 mg PO (n = 1) </paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"/><td styleCode="Rrule Botrule Lrule " valign="top"/><td styleCode="Rrule Botrule Lrule " valign="top"/><td styleCode="Rrule Botrule Lrule " valign="top"/></tr></tbody></table>
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions (5.1) ] . A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m 2 /day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown. The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis. Mutagenesis No evidence of genotoxicity was seen in bacterial ( Salmonella and E. coli ) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Impairment of Fertility Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m 2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions (5.1) ] . A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m 2 /day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown. The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis. Mutagenesis No evidence of genotoxicity was seen in bacterial ( Salmonella and E. coli ) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Impairment of Fertility Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m 2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
14 CLINICAL STUDIES 14.1 Kidney Transplantation Tacrolimus/Azathioprine (AZA) Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded. There were 205 patients randomized to tacrolimus-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids, and azathioprine. Overall, 1-year patient and graft survivals were 96.1% and 89.6%, respectively. Data from this trial of tacrolimus in conjunction with azathioprine indicate that during the first 3 months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year. Tacrolimus/Mycophenolate Mofetil (MMF) Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multicenter trial (Study 1), 1589 kidney transplant patients received tacrolimus (Group C, n = 401), sirolimus (Group D, n = 399), or one of two cyclosporine (CsA) regimens (Group A, n = 390 and Group B, n = 399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving tacrolimus/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the tacrolimus group exhibited higher estimated creatinine clearance rates (eCL cr ) using the Cockcroft-Gault formula (Table 20) and experienced fewer efficacy failures, defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or loss to follow-up (Table 21) in comparison to each of the other three groups. Patients randomized to tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions (6.1) ]. Table 18. Estimated Creatinine Clearance at 12 Months (Study 1) Group eCL cr [mL/min] at Month 12 All death/graft loss (n = 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n = 10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. N MEAN SD MEDIAN Treatment Difference with Group C (99.2% CI Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
ubjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. N MEAN SD MEDIAN Treatment Difference with Group C (99.2% CI Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. ) (A) CsA/MMF/CS 390 56.5 25.8 56.9 -8.6 (-13.7, -3.7) (B) CsA/MMF/CS/Daclizumab 399 58.9 25.6 60.9 -6.2 (-11.2, -1.2) (C) Tac/MMF/CS/Daclizumab 401 65.1 27.4 66.2 - (D) Siro/MMF/CS/Daclizumab 399 56.2 27.4 57.3 -8.9 (-14.1, -3.9) Total 1589 59.2 26.8 60.5 Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus Table 19. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1) Group A N = 390 Group B N = 399 Group C N = 401 Group D N = 399 Overall Failure 141 (36.2%) 126 (31.6%) 82 (20.4%) 185 (46.4%) Components of efficacy failure BPAR 113 (29.0%) 106 (26.6%) 60 (15.0%) 152 (38.1%) Graft loss excluding death 28 (7.2%) 20 (5.0%) 12 (3.0%) 30 (7.5%) Mortality 13 (3.3%) 7 (1.8%) 11 (2.7%) 12 (3.0%) Lost to follow-up 5 (1.3%) 7 (1.8%) 5 (1.3%) 6 (1.5%) Treatment Difference of efficacy failure compared to Group C (99.2% CI Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. ) 15.8% (7.1%, 24.3%) 11.2% (2.7%, 19.5%) - 26.0% (17.2%, 34.7%) Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab The protocol-specified target tacrolimus trough concentrations (C trough , Tac ) were 3-7 ng/mL; however, the observed median C troughs , Tac approximated 7 ng/mL throughout the 12-month trial (Table 22). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant. Table 20. Tacrolimus Whole Blood Trough Concentration Range (Study 1) Time Median (P10-P90 10 to 90 th Percentile: range of C trough, Tac that excludes lowest 10% and highest 10% of C trough, Tac ) tacrolimus whole blood trough concentration range (ng/mL) Day 30 (N = 366) 6.9 (4.4 – 11.3) Day 90 (N = 351) 6.8 (4.1 – 10.7) Day 180 (N = 355) 6.5 (4.0 – 9.6) Day 365 (N = 346) 6.5 (3.8 – 10.0) The protocol-specified target cyclosporine trough concentrations (C trough , CsA ) for Group B were 50-100 ng/mL; however, the observed median C troughs , CsA approximated 100 ng/mL throughout the 12-month trial. The protocol-specified target C troughs , CsA for Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median C troughs , CsA approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12. While patients in all groups started MMF at 1 gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 23); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions. Table 21. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1) Time period (Days) Time-averaged MMF dose (grams per day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.
mus/MMF (Group C) (Study 1) Time period (Days) Time-averaged MMF dose (grams per day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. Less than 2.0 2.0 Greater than 2.0 0-30 (N = 364) 37% 60% 2% 0-90 (N = 373) 47% 51% 2% 0-180 (N = 377) 56% 42% 2% 0-365 (N = 380) 63% 36% 1% Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) In a second randomized, open-label, multicenter trial (Study 2), 424 kidney transplant patients received tacrolimus (N = 212) or cyclosporine (N = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the tacrolimus/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving tacrolimus/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to over-immunosuppression (Table 24). Table 22. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2) Tacrolimus/MMF (N = 212) Cyclosporine/MMF (N = 212) Overall Failure 32 (15.1%) 36 (17.0%) Components of efficacy failure BPAR 16 (7.5%) 29 (13.7%) Graft loss excluding death 6 (2.8%) 4 (1.9%) Mortality 9 (4.2%) 5 (2.4%) Lost to follow-up 4 (1.9%) 1 (0.5%) Treatment Difference of efficacy failure compared to Tacrolimus/MMF group (95% CI 95% confidence interval calculated using Fisher's Exact Test. ) 1.9% (-5.2%, 9.0%) The protocol-specified target tacrolimus whole blood trough concentrations (C trough , Tac ) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median C troughs , Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 25). Approximately 80% of patients maintained tacrolimus whole blood trough concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year. Table 23. Tacrolimus Whole Blood Trough Concentration Range (Study 2) Time Median (P10-P90 10 to 90 th Percentile: range of C trough, Tac that excludes lowest 10% and highest 10% of C trough, Tac. ) tacrolimus whole blood trough concentration range (ng/mL) Day 30 (N = 174) 10.5 (6.3 – 16.8) Day 60 (N = 179) 9.2 (5.9 – 15.3) Day 120 (N = 176) 8.3 (4.6 – 13.3) Day 180 (N = 171) 7.8 (5.5 – 13.2) Day 365 (N = 178) 7.1 (4.2 – 12.4) The protocol-specified target cyclosporine whole blood concentrations (C trough , CsA ) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median C troughs , CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12. Patients in both groups started MMF at 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the tacrolimus/MMF group (Table 26) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the tacrolimus/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions (6.1) ]. Table 24. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2) Time period (Days) Time-averaged MMF dose (g/day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods.
Time in the Tacrolimus/MMF Group (Study 2) Time period (Days) Time-averaged MMF dose (g/day) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods. Less than 2.0 2.0 Greater than 2.0 0-30 (N = 212) 25% 69% 6% 0-90 (N = 212) 41% 53% 6% 0-180 (N = 212) 52% 41% 7% 0-365 (N = 212) 62% 34% 4% Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) 14.2 Liver Transplantation The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation. In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed. In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases. One-year patient survival and graft survival in the tacrolimus-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and tacrolimus-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and tacrolimus-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral tacrolimus dosing was 2 days. Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients are often maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL. 14.3 Heart Transplantation Two open-label, randomized, comparative trials evaluated the safety and efficacy of tacrolimus-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with tacrolimus or cyclosporine modified for 18 months. In a 3-arm trial conducted in the U.S., 331 patients received corticosteroids and tacrolimus plus sirolimus, tacrolimus plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year.
ibody induction, corticosteroids, and azathioprine in combination with tacrolimus or cyclosporine modified for 18 months. In a 3-arm trial conducted in the U.S., 331 patients received corticosteroids and tacrolimus plus sirolimus, tacrolimus plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year. In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the tacrolimus plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from 1 week to 3 months post-transplant, approximately 80% of patients maintained trough concentrations between 8 to 20 ng/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to 18 ng/mL. The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose tacrolimus; however, this regimen was associated with increased risk of wound-healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions (5.10) ] .
<table ID="_RefID0E51BK" width="100%"><caption>Table 18. Estimated Creatinine Clearance at 12 Months (Study 1)</caption><col width="33%"/><col width="10%"/><col width="11%"/><col width="10%"/><col width="12%"/><col width="25%"/><tbody><tr><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Group</content></paragraph></td><td align="center" colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">eCL <sub>cr</sub>[mL/min] at Month 12 </content><footnote ID="_Ref523389373">All death/graft loss (n = 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n = 10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing.
erular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. </footnote></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">MEAN</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">SD</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">MEDIAN</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Treatment Difference with Group C</content> <content styleCode="bold">(99.2% CI</content><footnote ID="_Ref523389461">Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.</footnote><content styleCode="bold">)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(A) CsA/MMF/CS</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>390</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-8.6 (-13.7, -3.7)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(B) CsA/MMF/CS/Daclizumab</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>399</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>58.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25.6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-6.2 (-11.2, -1.2)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(C) Tac/MMF/CS/Daclizumab</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>401</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>65.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27.4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>66.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(D) Siro/MMF/CS/Daclizumab</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>399</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27.4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>57.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-8.9 (-14.1, -3.9)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Total</paragraph></td><td align="center
td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>57.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-8.9 (-14.1, -3.9)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Total</paragraph></td><td align="center " styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1589</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>59.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60.5</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td colspan="6" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus</paragraph></td></tr></tbody></table> <table ID="_RefID0EMCCK" width="100%"><caption>Table 19.
" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1589</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>59.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60.5</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td colspan="6" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus</paragraph></td></tr></tbody></table> <table ID="_RefID0EMCCK" width="100%"><caption>Table 19. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1)</caption><col width="26%"/><col width="20%"/><col width="19%"/><col width="16%"/><col width="20%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Group A</content> <content styleCode="bold">N = 390</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Group B</content> <content styleCode="bold">N = 399</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Group C</content> <content styleCode="bold">N = 401</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Group D</content> <content styleCode="bold">N = 399</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Overall Failure</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>141 (36.2%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>126 (31.6%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>82 (20.4%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>185 (46.4%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Components of efficacy failure</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> BPAR</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>113 (29.0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>106 (26.6%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60 (15.0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>152 (38.1%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Graft loss excluding death</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28 (7.2%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20 (5.0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12 (3.0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30 (7.5%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Mortality</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13 (3.3%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (1.8%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (2.7%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12 (3.0%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lost to follow-up</paragraph></td><td align="center" st
"center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (2.7%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12 (3.0%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lost to follow-up</paragraph></td><td align="center" st yleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (1.3%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (1.8%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (1.3%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (1.5%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Treatment Difference of efficacy failure compared to Group C (99.2% CI <footnote ID="_Ref523389550">Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.</footnote>) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15.8%</paragraph><paragraph>(7.1%, 24.3%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11.2% (2.7%, 19.5%) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26.0% (17.2%, 34.7%) </paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab</paragraph></td></tr></tbody></table>
ode="Rrule Lrule Botrule " valign="top"><paragraph>26.0% (17.2%, 34.7%) </paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab</paragraph></td></tr></tbody></table> <table ID="_RefID0EIKCK" width="100%"><caption>Table 20. Tacrolimus Whole Blood Trough Concentration Range (Study 1)</caption><col width="31%"/><col width="69%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Time</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Median (P10-P90</content><footnote ID="_Ref523389600">10 to 90 th Percentile: range of C trough, Tac that excludes lowest 10% and highest 10% of C trough, Tac</footnote><content styleCode="bold">) tacrolimus whole blood trough concentration range (ng/mL)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Day 30 (N = 366)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6.9 (4.4 – 11.3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Day 90 (N = 351)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6.8 (4.1 – 10.7)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Day 180 (N = 355)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6.5 (4.0 – 9.6)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Day 365 (N = 346)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6.5 (3.8 – 10.0)</paragraph></td></tr></tbody></table>
Lrule Botrule " valign="top"><paragraph>6.5 (4.0 – 9.6)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Day 365 (N = 346)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6.5 (3.8 – 10.0)</paragraph></td></tr></tbody></table> <table ID="_RefID0EHNCK" width="100%"><caption>Table 21. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Time period (Days)</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Time-averaged MMF dose (grams per day)</content><footnote ID="_Ref523389752">Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.</footnote></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Less than 2.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Greater than 2.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0-30 (N = 364)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0-90 (N = 373)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>51%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0-180 (N = 377)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0-365 (N = 380)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>63%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</paragraph></td></tr></tbody></table>
op"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</paragraph></td></tr></tbody></table> <table ID="_RefID0EORCK" width="100%"><caption>Table 22. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2)</caption><col width="52%"/><col width="24%"/><col width="24%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/MMF</content></paragraph><paragraph><content styleCode="bold">(N = 212)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/MMF</content></paragraph><paragraph><content styleCode="bold">(N = 212)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Overall Failure</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32 (15.1%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36 (17.0%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Components of efficacy failure</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> BPAR</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16 (7.5%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29 (13.7%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Graft loss excluding death</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (2.8%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (1.9%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Mortality</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (4.2%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (2.4%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lost to follow-up</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (1.9%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Treatment Difference of efficacy failure compared to Tacrolimus/MMF group (95% CI <footnote ID="_Ref523389862">95% confidence interval calculated using Fisher's Exact Test.</footnote>) </paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1.9% (-5.2%, 9.0%)</paragraph></td></tr></tbody></table>
oup (95% CI <footnote ID="_Ref523389862">95% confidence interval calculated using Fisher's Exact Test.</footnote>) </paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1.9% (-5.2%, 9.0%)</paragraph></td></tr></tbody></table> <table ID="_RefID0EBWCK" width="100%"><caption>Table 23. Tacrolimus Whole Blood Trough Concentration Range (Study 2)</caption><col width="33%"/><col width="67%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Time</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Median (P10-P90</content><footnote ID="_Ref523389904">10 to 90 th Percentile: range of C trough, Tac that excludes lowest 10% and highest 10% of C trough, Tac.</footnote><content styleCode="bold">) tacrolimus whole blood trough concentration range (ng/mL)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Day 30 (N = 174)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10.5 (6.3 – 16.8)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Day 60 (N = 179)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9.2 (5.9 – 15.3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Day 120 (N = 176)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8.3 (4.6 – 13.3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Day 180 (N = 171)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.8 (5.5 – 13.2)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Day 365 (N = 178)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7.1 (4.2 – 12.4)</paragraph></td></tr></tbody></table>
rule Botrule " valign="top"><paragraph>7.8 (5.5 – 13.2)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Day 365 (N = 178)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7.1 (4.2 – 12.4)</paragraph></td></tr></tbody></table> <table ID="_RefID0EJZCK" width="100%"><caption>Table 24. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2)</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Time period (Days)</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Time-averaged MMF dose (g/day)</content><footnote ID="_Ref523389943">Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods.</footnote></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Less than 2.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Greater than 2.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0-30 (N = 212)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>69%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0-90 (N = 212)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>41%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>53%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0-180 (N = 212)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>52%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>41%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0-365 (N = 212)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>62%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</paragraph></td></tr></tbody></table>
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Tacrolimus Capsules Tacrolimus Capsules, USP are available containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus, USP. The 0.5 mg capsules are hard-shell gelatin capsules with a light orange opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLAN over 2045 in black ink on both the cap and the body. They are available as follows: NDC 48433-092-20 – Unit dose blister packages of 100 (10 cards of 10 capsules each). The 1 mg capsules are hard-shell gelatin capsules with a light blue opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLAN over 2046 in black ink on both the cap and the body. They are available as follows: NDC 48433-093-20 – Unit dose blister packages of 100 (10 cards of 10 capsules each). The 5 mg capsules are hard-shell gelatin capsules with a rubine red opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLAN over 2047 in black ink on both the cap and the body. They are available as follows: NDC 48433-094-20 – Unit dose blister packages of 100 (10 cards of 10 capsules each). Store and Dispense: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. 16.4 Handling and Disposal Tacrolimus can cause fetal harm. Tacrolimus capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in tacrolimus capsules. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures 1 .
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). 17.1 Administration Advise the patient or caregiver to: Inspect their tacrolimus capsules medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for tacrolimus capsules. Take tacrolimus capsules at the same 12-hour intervals every day to achieve consistent blood concentrations. Take tacrolimus capsules consistently either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus. Not to eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions (7.2) ] . 17.2 Development of Lymphoma and Other Malignancies Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Warnings and Precautions (5.1) ] . 17.3 Increased Risk of Infection Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Warnings and Precautions (5.2) ] . 17.4 New Onset Diabetes After Transplant Inform patients that tacrolimus capsules can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst, or hunger [see Warnings and Precautions (5.4) ] . 17.5 Nephrotoxicity Inform patients that tacrolimus can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions (5.5) ] . 17.6 Neurotoxicity Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions (5.6) ] . 17.7 Hyperkalemia Inform patients that tacrolimus can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions (5.7) ]. 17.8 Hypertension Inform patients that tacrolimus can cause high blood pressure which may require treatment with antihypertensive therapy. Advise patients to monitor their blood pressure [see Warnings and Precautions (5.8) ]. 17.9 Thrombotic Microangiopathy Inform patients that tacrolimus can cause blood clotting problems. The risk of this occurring increases when patients take tacrolimus and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria [see Warnings and Precautions (5.16) ] .
sk of this occurring increases when patients take tacrolimus and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria [see Warnings and Precautions (5.16) ] . 17.10 Drug Interactions Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription medicines and nonprescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice [see Drug Interactions (7) ] . 17.11 Pregnancy, Lactation and Infertility Inform women of childbearing potential that tacrolimus can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations (8.1 , 8.2 , 8.3) ] . Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ [see Use in Specific Populations (8.1) ] . Based on animal studies, tacrolimus may affect fertility in males and females [see Nonclinical Toxicology (13.1) ] . 17.12 Myocardial Hypertrophy Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure). 17.13 Immunizations Inform patients that tacrolimus can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.14) ] .
Patient Information Tacrolimus Capsules, USP, for oral use (ta kroe′ li mus) Read this Patient Information before you start taking tacrolimus capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about tacrolimus capsules? Tacrolimus capsules can cause serious side effects, including: Increased risk of cancer. People who take tacrolimus capsules have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma). Increased risk of infection. Tacrolimus capsules are a medicine that affect your immune system. Tacrolimus capsules can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving tacrolimus capsules that can cause death. Call your healthcare provider right away if you have any symptoms of an infection, including: fever sweats or chills cough or flu-like symptoms muscle aches warm, red, or painful areas on your skin What are tacrolimus capsules? Tacrolimus capsules are a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant. Tacrolimus capsules are a type of tacrolimus immediate-release drug and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you. Who should not take tacrolimus capsules? Do not take tacrolimus capsules if you: are allergic to tacrolimus or any of the ingredients in tacrolimus capsules. See the end of this leaflet for a complete list of ingredients in tacrolimus capsules. What should I tell my healthcare provider before taking tacrolimus capsules? Before taking tacrolimus capsules, tell your healthcare provider about all of your medical conditions, including if you: plan to receive any vaccines. People taking tacrolimus capsules should not receive live vaccines. have or have had liver, kidney, or heart problems. are pregnant or plan to become pregnant. Tacrolimus capsules can harm your unborn baby. If you are able to become pregnant, you should use effective birth control before and during treatment with tacrolimus capsules. Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you. Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus capsules. Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you. There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with tacrolimus capsules. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/. are breastfeeding or plan to breastfeed. Tacrolimus passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking tacrolimus capsules. plan to have children. Tacrolimus capsules may affect the ability to have children in females and males (fertility problems).
ry.org/. are breastfeeding or plan to breastfeed. Tacrolimus passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking tacrolimus capsules. plan to have children. Tacrolimus capsules may affect the ability to have children in females and males (fertility problems). Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine, including prescription and over-the-counter medicines, vitamins, natural, herbal, or nutritional supplements. Especially tell your healthcare provider if you take: sirolimus (RAPAMUNE ® ): You should not take tacrolimus capsules if you take sirolimus. cyclosporine (GENGRAF ® , NEORAL ® , and SANDIMUNE ® ) medicines called aminoglycosides that are used to treat bacterial infections ganciclovir (CYTOVENE ® IV, VALCYTE ® ) amphotericin B (ABELCET ® , AMBISOME ® ) cisplatin antiviral medicines called nucleoside reverse transcriptase inhibitors antiviral medicines called protease inhibitors water pill (diuretic) medicine to treat high blood pressure nelfinavir (VIRACEPT ® ) telaprevir (INCIVEK ® ) boceprevir ritonavir (KALETRA ® , NORVIR ® , TECHNIVIE TM , VIEKIRA PAK TM , VIEKIRA, XR TM ) letermovir (PREVYMIS TM ) ketoconazole itraconazole (ONMEL TM , SPORANOX ® ) voriconazole (VFEND ® ) caspofungin (CANCIDAS ® ) clarithromycin (BIAXIN ® , BIAXIN XL ® , PREVPAC ® ) rifampin (RIFADIN ® , RIFAMATE ® , RIFATER ® , RIMACTANE ® ) rifabutin (MYCOBUTIN ® ) amiodarone (NEXTERONE ® , PACERONE ® ) cannabidiol (EPIDIOLEX ® ) Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. Tacrolimus capsules may affect the way other medicines work, and other medicines may affect how tacrolimus capsules work. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take tacrolimus capsules? Take tacrolimus capsules exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many tacrolimus capsules to take and when to take them. Your healthcare provider may change your tacrolimus capsules dose if needed. Do not stop taking or change your dose of tacrolimus capsules without talking to your healthcare provider. Take tacrolimus capsules with or without food. Take tacrolimus capsules the same way every day. For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food. Take tacrolimus capsules at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m. Taking tacrolimus capsules at the same time each day helps to keep the amount of medicine in your body at a steady level. If you take too many tacrolimus capsules, call your healthcare provider or go to the nearest hospital emergency room right away. Tacrolimus capsules: Do not open or crush tacrolimus capsules. What should I avoid while taking tacrolimus capsules? While you take tacrolimus capsules you should not receive any live vaccines. Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF). Do not eat grapefruit or drink grapefruit juice during treatment with tacrolimus capsules. What are the possible side effects of tacrolimus capsules? Tacrolimus capsules may cause serious side effects, including: See “What is the most important information I should know about tacrolimus capsules?” problems from medicine errors. People who take tacrolimus capsules have sometimes been given the wrong type of tacrolimus product.
ble side effects of tacrolimus capsules? Tacrolimus capsules may cause serious side effects, including: See “What is the most important information I should know about tacrolimus capsules?” problems from medicine errors. People who take tacrolimus capsules have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as tacrolimus capsules and cannot be substituted for each other. Check your tacrolimus capsules when you get a new prescription and before you take it to make sure you have received tacrolimus capsules . Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine. high blood sugar (diabetes). Your healthcare provider may do blood tests to check for diabetes while you take tacrolimus capsules. Call your healthcare provider right away if you have any symptoms of high blood sugar, including: frequent urination increased thirst or hunger blurred vision confusion drowsiness loss of appetite fruity smell on your breath nausea, vomiting, or stomach pain kidney problems. Kidney problems are a serious and common side effect of tacrolimus capsules. Your healthcare provider may do blood tests to check your kidney function while you take tacrolimus capsules. nervous system problems. Nervous system problems are a serious and common side effect of tacrolimus capsules. Call your healthcare provider right away if you get any of these symptoms while taking tacrolimus capsules. These could be signs of a serious nervous system problem: headache confusion seizures changes in your vision changes in behavior coma tremors numbness and tingling high levels of potassium in your blood. Your healthcare provider may do blood tests to check your potassium level while you take tacrolimus capsules. high blood pressure. High blood pressure is a serious and common side effect of tacrolimus capsules. Your healthcare provider will monitor your blood pressure while you take tacrolimus capsules and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home. changes in the electrical activity of your heart (QT prolongation). heart problems (myocardial hypertrophy). Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking tacrolimus capsules: shortness of breath chest pain feel lightheaded feel faint severe low red blood cell count (anemia). blood clotting problems: Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase. The most common side effects of tacrolimus capsules in people who have received a kidney, liver, or heart transplant are: infections in general, including cytomegalovirus (cmv) infection tremors (shaking of the body) constipation diarrhea headache stomach pain trouble sleeping nausea high blood sugar (diabetes) low levels of magnesium in your blood low levels of phosphate in your blood swelling of the hands, legs, ankles, or feet weakness pain high levels of fat in your blood high levels of potassium in your blood low red blood cell count (anemia) low white blood cell count fever numbness or tingling in your hands and feet inflammation of your airway (bronchitis) fluid around your heart Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of tacrolimus capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects.
itis) fluid around your heart Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of tacrolimus capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store tacrolimus capsules? Tacrolimus capsules Store tacrolimus capsules at room temperature between 20° to 25°C (68° to 77°F). Keep tacrolimus capsules and all medicines out of the reach of children. General information about the safe and effective use of tacrolimus capsules. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tacrolimus capsules for a condition for which they were not prescribed. Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about tacrolimus capsules that is written for health professionals. This Patient Information leaflet summarizes the most important information about tacrolimus capsules. If you would like more information, talk to your healthcare provider. What are the ingredients in tacrolimus capsules? Active ingredient: tacrolimus Inactive ingredients: Tacrolimus capsules: anhydrous lactose, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. The 0.5 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules also contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules also contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10. In addition, the black imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. The brands listed are trademarks of their respective owners. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Manufactured by: Haupt Pharma Amareg GmbH Donaustaufer Strasse 378 Regensburg, Bayern, 93055, Germany Distributed by: Safecor Health LLC Rockford, IL 61103 U.S.A. Revised: 8/2025 HPT:TACR:R4ppb/HPT:PL:TACR:R2ppb
<table width="100%"><col width="2%"/><col width="45%"/><col width="52%"/><tbody><tr><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus Capsules, USP, for oral use</content></paragraph><paragraph><content styleCode="bold">(ta kroe′ li mus)</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Read this Patient Information before you start taking tacrolimus capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about tacrolimus capsules?</content></paragraph><paragraph><content styleCode="bold">Tacrolimus capsules can cause serious side effects, including:</content></paragraph><list listType="unordered"><item><content styleCode="bold">Increased risk of cancer.</content>People who take tacrolimus capsules have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma). </item><item><content styleCode="bold">Increased risk of infection.</content>Tacrolimus capsules are a medicine that affect your immune system. Tacrolimus capsules can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving tacrolimus capsules that can cause death. <content styleCode="bold">Call your healthcare provider right away if you have any symptoms of an infection, including:</content></item></list></td></tr><tr><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Botrule " valign="top"><list listType="unordered"><item>fever</item><item>sweats or chills</item><item>cough or flu-like symptoms</item></list></td><td styleCode="Rrule Botrule " valign="top"><list listType="unordered"><item>muscle aches</item><item>warm, red, or painful areas on your skin</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are tacrolimus capsules?</content></paragraph><list listType="unordered"><item>Tacrolimus capsules are a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant.</item><item>Tacrolimus capsules are a type of tacrolimus immediate-release drug and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Who should not take tacrolimus capsules?</content></paragraph><paragraph><content styleCode="bold">Do not take tacrolimus capsules if you:</content></paragraph><list listType="unordered"><item>are allergic to tacrolimus or any of the ingredients in tacrolimus capsules.
valign="top"><paragraph><content styleCode="bold">Who should not take tacrolimus capsules?</content></paragraph><paragraph><content styleCode="bold">Do not take tacrolimus capsules if you:</content></paragraph><list listType="unordered"><item>are allergic to tacrolimus or any of the ingredients in tacrolimus capsules. See the end of this leaflet for a complete list of ingredients in tacrolimus capsules.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I tell my healthcare provider before taking tacrolimus capsules?</content></paragraph><paragraph><content styleCode="bold">Before taking tacrolimus capsules, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item>plan to receive any vaccines. People taking tacrolimus capsules should not receive live vaccines.</item><item>have or have had liver, kidney, or heart problems.</item><item>are pregnant or plan to become pregnant. Tacrolimus capsules can harm your unborn baby. <list listType="unordered"><item>If you are able to become pregnant, you should use effective birth control before and during treatment with tacrolimus capsules. Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you.</item><item>Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus capsules. Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you.</item><item>There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with tacrolimus capsules. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/.</item></list></item><item>are breastfeeding or plan to breastfeed. Tacrolimus passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking tacrolimus capsules.</item><item>plan to have children. Tacrolimus capsules may affect the ability to have children in females and males (fertility problems).</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine,</content>including prescription and over-the-counter medicines, vitamins, natural, herbal, or nutritional supplements. </paragraph><paragraph><content styleCode="bold">Especially tell your healthcare provider if you take:</content></paragraph><list listType="unordered"><item>sirolimus (RAPAMUNE <sup>®</sup>): You should not take tacrolimus capsules if you take sirolimus.
ines, vitamins, natural, herbal, or nutritional supplements. </paragraph><paragraph><content styleCode="bold">Especially tell your healthcare provider if you take:</content></paragraph><list listType="unordered"><item>sirolimus (RAPAMUNE <sup>®</sup>): You should not take tacrolimus capsules if you take sirolimus. </item><item>cyclosporine (GENGRAF <sup>®</sup>, NEORAL <sup>®</sup>, and SANDIMUNE <sup>®</sup>) </item><item>medicines called aminoglycosides that are used to treat bacterial infections</item><item>ganciclovir (CYTOVENE <sup>®</sup>IV, VALCYTE <sup>®</sup>) </item><item>amphotericin B (ABELCET <sup>®</sup>, AMBISOME <sup>®</sup>) </item><item>cisplatin</item><item>antiviral medicines called nucleoside reverse transcriptase inhibitors</item><item>antiviral medicines called protease inhibitors</item><item>water pill (diuretic)</item><item>medicine to treat high blood pressure</item><item>nelfinavir (VIRACEPT <sup>®</sup>) </item><item>telaprevir (INCIVEK <sup>®</sup>) </item><item>boceprevir</item><item>ritonavir (KALETRA <sup>®</sup>, NORVIR <sup>®</sup>, TECHNIVIE <sup>TM</sup>, VIEKIRA PAK <sup>TM</sup>, VIEKIRA, XR <sup>TM</sup>) </item><item>letermovir (PREVYMIS <sup>TM</sup>) </item><item>ketoconazole</item><item>itraconazole (ONMEL <sup>TM</sup>, SPORANOX <sup>®</sup>) </item><item>voriconazole (VFEND <sup>®</sup>) </item><item>caspofungin (CANCIDAS <sup>®</sup>) </item><item>clarithromycin (BIAXIN <sup>®</sup>, BIAXIN XL <sup>®</sup>, PREVPAC <sup>®</sup>) </item><item>rifampin (RIFADIN <sup>®</sup>, RIFAMATE <sup>®</sup>, RIFATER <sup>®</sup>, RIMACTANE <sup>®</sup>) </item><item>rifabutin (MYCOBUTIN <sup>®</sup>) </item><item>amiodarone (NEXTERONE <sup>®</sup>, PACERONE <sup>®</sup>) </item><item>cannabidiol (EPIDIOLEX <sup>®</sup>) </item></list><paragraph>Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above.</paragraph><paragraph>Tacrolimus capsules may affect the way other medicines work, and other medicines may affect how tacrolimus capsules work.</paragraph><paragraph>Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take tacrolimus capsules?</content></paragraph><list listType="unordered"><item>Take tacrolimus capsules exactly as your healthcare provider tells you to take them.</item><item>Your healthcare provider will tell you how many tacrolimus capsules to take and when to take them. Your healthcare provider may change your tacrolimus capsules dose if needed. <content styleCode="bold">Do not</content>stop taking or change your dose of tacrolimus capsules without talking to your healthcare provider. </item><item>Take tacrolimus capsules with or without food.</item><item>Take tacrolimus capsules the same way every day. For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food.</item><item>Take tacrolimus capsules at the same time each day, 12 hours apart.
</item><item>Take tacrolimus capsules with or without food.</item><item>Take tacrolimus capsules the same way every day. For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food.</item><item>Take tacrolimus capsules at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m.</item><item>Taking tacrolimus capsules at the same time each day helps to keep the amount of medicine in your body at a steady level.</item><item>If you take too many tacrolimus capsules, call your healthcare provider or go to the nearest hospital emergency room right away.</item></list><paragraph><content styleCode="bold">Tacrolimus capsules:</content></paragraph><list listType="unordered"><item><content styleCode="bold">Do not</content>open or crush tacrolimus capsules. </item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I avoid while taking tacrolimus capsules?</content></paragraph><list listType="unordered"><item>While you take tacrolimus capsules you should not receive any live vaccines.</item><item>Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).</item><item><content styleCode="bold">Do not</content> eat grapefruit or drink grapefruit juice during treatment with tacrolimus capsules. </item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of tacrolimus capsules?</content></paragraph><paragraph><content styleCode="bold">Tacrolimus capsules may cause serious side effects, including:</content></paragraph><list listType="unordered"><item>See <content styleCode="bold">“What is the most important information I should know about tacrolimus capsules?”</content></item><item><content styleCode="bold">problems from medicine errors.</content>People who take tacrolimus capsules have sometimes been given the wrong type of tacrolimus product. <content styleCode="bold">Tacrolimus extended-release medicines are not the same as tacrolimus capsules </content>and cannot be substituted for each other. <content styleCode="bold">Check your tacrolimus capsules when you get a new prescription and before you take it to make sure you have received tacrolimus capsules</content>. </item><item>Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine.</item><item><content styleCode="bold">high blood sugar (diabetes).</content>Your healthcare provider may do blood tests to check for diabetes while you take tacrolimus capsules. Call your healthcare provider right away if you have any symptoms of high blood sugar, including: </item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item>frequent urination</item><item>increased thirst or hunger</item><item>blurred vision</item><item>confusion</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item>drowsiness</item><item>loss of appetite</item><item>fruity smell on your breath</item><item>nausea, vomiting, or stomach pain</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><content styleCode="bold">kidney problems.</content>Kidney problems are a serious and common side effect of tacrolimus capsules. Your healthcare provider may do blood tests to check your kidney function while you take tacrolimus capsules.
olspan="3" styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><content styleCode="bold">kidney problems.</content>Kidney problems are a serious and common side effect of tacrolimus capsules. Your healthcare provider may do blood tests to check your kidney function while you take tacrolimus capsules. </item><item><content styleCode="bold">nervous system problems.</content>Nervous system problems are a serious and common side effect of tacrolimus capsules. Call your healthcare provider right away if you get any of these symptoms while taking tacrolimus capsules. These could be signs of a serious nervous system problem: </item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item>headache</item><item>confusion</item><item>seizures</item><item>changes in your vision</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item>changes in behavior</item><item>coma</item><item>tremors</item><item>numbness and tingling</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><content styleCode="bold">high levels of potassium in your blood.</content>Your healthcare provider may do blood tests to check your potassium level while you take tacrolimus capsules. </item><item><content styleCode="bold">high blood pressure.</content>High blood pressure is a serious and common side effect of tacrolimus capsules. Your healthcare provider will monitor your blood pressure while you take tacrolimus capsules and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home. </item><item><content styleCode="bold">changes in the electrical activity of your heart (QT prolongation).</content></item><item><content styleCode="bold">heart problems (myocardial hypertrophy).</content>Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking tacrolimus capsules: </item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item>shortness of breath</item><item>chest pain</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item>feel lightheaded</item><item>feel faint</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><content styleCode="bold">severe low red blood cell count (anemia).</content></item><item><content styleCode="bold">blood clotting problems:</content>Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase.
</content>Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase. </item></list><paragraph><content styleCode="bold">The most common side effects of tacrolimus capsules in people who have received a kidney, liver, or heart transplant are:</content></paragraph></td></tr><tr><td colspan="2" styleCode="Lrule " valign="top"><list listType="unordered"><item>infections in general, including cytomegalovirus (cmv) infection</item><item>tremors (shaking of the body)</item><item>constipation</item><item>diarrhea</item><item>headache</item><item>stomach pain</item><item>trouble sleeping</item><item>nausea</item><item>high blood sugar (diabetes)</item><item>low levels of magnesium in your blood</item><item>low levels of phosphate in your blood</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item>swelling of the hands, legs, ankles, or feet</item><item>weakness</item><item>pain</item><item>high levels of fat in your blood</item><item>high levels of potassium in your blood</item><item>low red blood cell count (anemia)</item><item>low white blood cell count</item><item>fever</item><item>numbness or tingling in your hands and feet</item><item>inflammation of your airway (bronchitis)</item><item>fluid around your heart</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</paragraph><paragraph>These are not all the possible side effects of tacrolimus capsules. For more information, ask your healthcare provider or pharmacist.</paragraph><paragraph><content styleCode="bold">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store tacrolimus capsules?</content></paragraph><paragraph><content styleCode="bold">Tacrolimus capsules</content></paragraph><list listType="unordered"><item>Store tacrolimus capsules at room temperature between 20° to 25°C (68° to 77°F).</item></list><paragraph><content styleCode="bold">Keep tacrolimus capsules and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of tacrolimus capsules.</content></paragraph><list listType="unordered"><item>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tacrolimus capsules for a condition for which they were not prescribed. Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about tacrolimus capsules that is written for health professionals.</item><item>This Patient Information leaflet summarizes the most important information about tacrolimus capsules.
even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about tacrolimus capsules that is written for health professionals.</item><item>This Patient Information leaflet summarizes the most important information about tacrolimus capsules. If you would like more information, talk to your healthcare provider.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in tacrolimus capsules?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content>tacrolimus </paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content></paragraph><paragraph>Tacrolimus capsules: anhydrous lactose, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.</paragraph><paragraph>The 0.5 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules also contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules also contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10.</paragraph><paragraph>In addition, the black imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.</paragraph><paragraph><content styleCode="bold">Manufactured for:</content>Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. </paragraph><paragraph>The brands listed are trademarks of their respective owners.</paragraph><paragraph>For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).</paragraph></td></tr></tbody></table>
WARNING: MALIGNANCIES AND SERIOUS INFECTIONS • Increased risk for developing serious infections and malignancies with tacrolimus or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 ) WARNING: MALIGNANCIES AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning . • Increased risk for developing serious infections and malignancies with tacrolimus or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 )
1 INDICATIONS AND USAGE Tacrolimus capsule is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult patients receiving allogeneic liver, kidney, or heart transplants, and pediatric patients receiving allogeneic liver transplants in combination with other immunosuppressants. ( 1.1 ) 1.1 Prophylaxis of Organ Rejection in Kidney, Liver or Heart Transplant Tacrolimus capsules are indicated for the prophylaxis of organ rejection, in adult patients receiving allogeneic kidney transplant [see Clinical Studies ( 14.1 )] , liver transplant [see Clinical Studies ( 14.2 )] , heart transplant [ see Clinical Studies ( 14.3 )] , and pediatric patients receiving allogeneic liver transplants [see Clinical Studies ( 14.2) ] in combination with other immunosuppressants. Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
<table width="100%"><col width="100%"/><tbody><tr><td styleCode="Botrule Toprule " valign="top"><paragraph>Tacrolimus capsule is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult patients receiving allogeneic liver, kidney, or heart transplants, and pediatric patients receiving allogeneic liver transplants in combination with other immunosuppressants. (<linkHtml href="#_a506de58-027a-4a29-4caa-c53c4fea5085">1.1</linkHtml>)</paragraph></td></tr></tbody></table>
2 DOSAGE AND ADMINISTRATION Intravenous (IV) use recommended for patients who cannot tolerate oralformulations (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 dosage adjustments for African-American patients (2.2) , hepatic and renal impaired. ( 2.4 , 2.5 ) • For complete dosing information, see Full Prescribing Information. ADULT Patient Population Initial OralDosage (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 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 Patient Population Initial Oral Dosage (formulation) Whole Blood Trough Concerntration Range 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 MMF= Mycophenolate mofetil 1 Patients with cystic fibrosis may require higher doses due to lower bioavailability. 2 Dose at 0.1 mg/kg/day if antibody induction treatment is administered. 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 Formulation (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)].
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 [see Drug Interactions ( 7.2 )] . Tacrolimus should not be used simultaneously with cyclosporine. Tacrolimus or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed. Therapeutic drug monitoring (TDM) is recommended for all patients receiving tacrolimus [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 capsule 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 1 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 2 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 1 African-American patients may require higher doses compared to Caucasians (see Table 2 ). 2 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 )]. Dosage should be titrated based on clinical assessments of rejection and tolerability. Tacrolimus capsule 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.
roids 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 N=114 African-American 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 Dosage Recommendations for Pediatric Liver Transplant Patients Oral formulation (capsules) Pediatric patients in general, need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole blood trough concentration range are shown in Table 3. Perform TDM to ensure that patients are within the ranges listed in Table 3. Table 3. Summary of Initial Tacrolimus Capsule Dosing Recommendations and Whole Blood Trough Concentration Range in Children Patient Population Initial Tacrolimus Capsule Dosing Whole Blood Trough Concentration Range Pediatric liver transplant patients 2 0.15 to 0.2 mg/kg/day capsules divided in two doses, administered every 12 hours Month 1 to 12: 5 to 20 ng/mL 2 . See Clinical Studies ( 14.2 ) , Liver Transplantation. For conversion of pediatric patients from tacrolimus for oral suspension to tacrolimus capsules or from tacrolimus capsules to tacrolimus for oral suspension, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration ( 2.6 )] . Intravenous Injection If a patient is unable to receive an oral formulation, the patient may be started on tacrolimus injection. For pediatric liver transplant patients, the intravenous dose is 0.03 to 0.05 mg/kg/day. Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
atric liver transplant patients, the intravenous dose is 0.03 to 0.05 mg/kg/day. Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Dosage Modification for Patients with Renal Impairment Due to its potential for nephrotoxicity, consider dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required. In kidney transplant patients with post-operative oliguria, the initial dose of tacrolimus capsules should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration ( 2.2 ) , Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.6 ) , and Clinical Pharmacology ( 12.3 )]. 2.5 Dosage Modification for Patients with Hepatic Impairment Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh ≥ 10) may require lower doses of tacrolimus capsules. Close monitoring of blood concentrations is warranted. The use of tacrolimus capsules in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. These patients should be monitored closely, and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.5) , Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )]. 2.6 Therapeutic Drug Monitoring Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Whole blood trough concentration range can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation. The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure. Methods commonly used for the assay of tacrolimus include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore, assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage.
with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer, they should be deep frozen at -20°C. One study showed drug recovery >90% for samples stored at -20°C for 6 months, with reduced recovery observed after 6 months.
3 DOSAGE FORMS AND STRENGTHS Tacrolimus Capsules USP, 0.5 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, dark yellow opaque cap imprinted with ‘0.5 MG’ and dark yellow opaque body imprinted with ‘RDY 525’using red ink. Tacrolimus Capsules USP, 1 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, white opaque cap imprinted with ‘1 MG’ and white opaque body imprinted with ‘RDY 526’using red ink. Tacrolimus Capsules USP, 5 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, dark grayish red opaque cap imprinted with ‘5 MG’ and dark grayish red opaque body imprinted with ‘RDY 527’ using white ink. • Capsules: 0.5 mg, 1 mg and 5 mg (3)
4 CONTRAINDICATIONS 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 [seeAdverse Reactions (6) ]. Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 )
5 WARNINGS AND PRECAUTIONS • Not Interchangeable with Extended-Release Tacrolimus Products-Medication Errors: Instruct patients or caregivers to recognize the appearance of tacrolimus capsules. ( 5.3 ) • New Onset Diabetes After Transplant: Monitor blood glucose. ( 5.4 ) • Nephrotoxicity (acute and/or chronic): Reduce the dose; use caution with other nephrotoxic drugs. ( 5.5 ) • Neurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue tacrolimus capsules. ( 5.6 ) • Hyperkalemia: Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia. ( 5.7 ) • Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions. ( 5.8 ) • Anaphylactic Reactions with IV formulation: Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis. ( 5.9 ) • Not recommended for use with sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions. ( 5.10 ) • Myocardial Hypertrophy: Consider dose reduction/discontinuation. ( 5.13 ) • Immunizations: Avoid live vaccines. ( 5.14 ) • Pure Red Cell Aplasia: Consider discontinuation of tacrolimus. ( 5.15 ) • Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.16 ) 5.1 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including tacrolimus, are at increased 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. As usual for patients with increased risk for skin cancer, examine patients for skin changes; exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein-Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment. 5.2 Serious Infections Patients receiving immunosuppressants, including tacrolimus, are at increased 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 (PVAN), mostly due to BK virus infection • JC virus-associated progressive multifocal leukoencephalopathy (PML) • Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing 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) ].
ransplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing 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 Not Interchangeable with Extended-Release Tacrolimus Products-Medication Errors Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under-or overexposure to tacrolimus. Tacrolimus is not interchangeable or substitutable for tacrolimus extended-release products. 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 dosage forms [see Dosage Forms and Strengths ( 3 ) ] and to confirm with the healthcare provider if a different product is dispensed. 5.4 New Onset Diabetes After Transplant Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver or heart transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using tacrolimus [see Adverse Reactions (6.1) ]. 5.5 Nephrotoxicity due to Tacrolimus capsules and Drug Interactions Tacrolimus, 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. Nephrotoxicity was reported in clinical trials [see Adverse Reactions ( 6.1) ]. 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 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 doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions ( 7.2 )]. 5.6 Neurotoxicity Tacrolimus 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 if neurotoxicity occurs. 5.7 Hyperkalemia Hyperkalemia has been reported with tacrolimus use. Serum potassium levels should be monitored.
ed with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of tacrolimus if neurotoxicity occurs. 5.7 Hyperkalemia Hyperkalemia has been reported with tacrolimus use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during tacrolimus therapy [see Adverse Reactions (6.1) ] . Monitor serum potassium levels periodically during treatment. 5.8 Hypertension Hypertension is a common adverse effect of tacrolimus therapy and may require antihypertensive therapy [see Adverse Reactions (6.1) ] . The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions ( 5.7 )] . Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [see Drug Interactions (7.2 )] . 5.9 Anaphylactic Reactions with Tacrolimus Injection Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take tacrolimus orally. Monitor patients for anaphylaxis when using the intravenous route of administration [see Dosage and Administratio n ( 2.1 )]. 5.10 Not Recommended for Use with Sirolimus Tacrolimus capsules are not recommended for use with sirolimus: • The use of sirolimus with tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT) and is not recommended. • The use of sirolimus (2 mg per day) with tacrolimus in heart transplant patients in a U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies ( 14.3 )]. • The use of sirolimus with tacrolimus capsules may increase the risk of thrombotic microangiopathy [see Warnings and Precautions ( 5.16 )]. 5.11 Interactions with CYP3A4 Inhibitors and Inducers When co-administering tacrolimus with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions (7.2) ]. 5.12 QT Prolongation Tacrolimus may prolong the QT/QTc interval and may cause Torsades de pointes . Avoid tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.
king certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. When co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of tacrolimus with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions ( 7.2 ) ]. 5.13 Myocardial Hypertrophy Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered [see Adverse Reactions (6.2) ]. 5.14 Immunizations Whenever possible, administer the complete complement of vaccines before transplantation and treatment with tacrolimus. The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: 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 tacrolimus. 5.15 Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of tacrolimus should be considered [see Adverse Reactions (6.2) ]. 5.16 Thrombotic Microangiopathy (Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura) Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with tacrolimus capsules. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA. In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA. 5.17 Cannabidiol Drug Interactions 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 Drug Interactions (7.3) ] .
6 ADVERSE REACTIONS The following serious and otherwise important 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 )] • New Onset Diabetes After Transplant [see Warnings and Precautions ( 5.4 ) ] • Nephrotoxicity [see Warnings and Precautions ( 5.5 )] • Neurotoxicity [see Warnings and Precautions ( 5.6 )] • Hyperkalemia [see Warnings and Precautions ( 5.7 )] • Hypertension [see Warnings and Precautions ( 5.8 )] • Anaphylactic Reactions with Tacrolimus Injection [see Warnings and Precautions ( 5.9 )] • Myocardial Hypertrophy [see Warnings and Precautions ( 5.13 )] • Pure Red Cell Aplasia [see Warnings and Precautions ( 5.15 )] • Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions ( 5.16) ] The most common adverse reactions (≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 Transplantation The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression. Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received tacrolimus-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean±SD was 43±13 years on tacrolimus and 44±12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12 month post-transplant information from this trial is presented below. The most common adverse reactions (≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.
ain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below: Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) Tacrolimus/AZA (N=205) Cyclosporine/AZA (N=207) Nervous System Tremor Headache Insomnia Paresthesia Dizziness 54% 44% 32% 23% 19% 34% 38% 30% 16% 16% Gastrointestinal Diarrhea Nausea Constipation Vomiting Dyspepsia 44% 38% 35% 29% 28% 41% 36% 43% 23% 20% Cardiovascular Hypertension Chest Pain 50% 19% 52% 13% Urogenital Creatinine Increased Urinary Tract Infection 45% 34% 42% 35% Metabolic and Nutritional Hypophosphatemia Hypomagnesemia Hyperlipemia Hyperkalemia Diabetes Mellitus Hypokalemia Hyperglycemia Edema 49% 34% 31% 31% 24% 22% 22% 18% 53% 17% 38% 32% 9% 25% 16% 19% Hemic and Lymphatic Anemia Leukopenia 30% 15% 24% 17% Miscellaneous Infection 45% 49% Peripheral Edema Asthenia Abdominal Pain Pain Fever Back Pain 36% 34% 33% 32% 29% 24% 48% 30% 31% 30% 29% 20% Respiratory System Dyspnea Cough Increased 22% 18% 18% 15% Musculoskeletal Arthralgia 25% 24% Skin Rash Pruritus 17% 15% 12% 7% Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n=403), or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12 month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below: Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1) Tacrolimus Cyclosporine Cyclosporine (Group C) (Group A) (Group B) (N=403) (N=384) (N=408) Diarrhea 25% 16% 13% Urinary Tract Infection 24% 28% 24% Anemia 17% 19% 17% Hypertension 13% 14% 12% Leukopenia 13% 10% 10% Edema Peripheral 11% 12% 13% Hyperlipidemia 10% 15% 13% Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n=212) or cyclosporine (n=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below.
twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below: Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2) Tacrolimus/MMF Cyclosporine/MMF (N=212) (N=212) Gastrointestinal Disorders Diarrhea 44% 26% Nausea 39% 47% Constipation 36% 41% Vomiting 26% 25% Dyspepsia 18% 15% Injury, Poisoning, and Procedural Complications Post-Procedural Pain 29% 27% Incision Site Complication 28% 23% Graft Dysfunction 24% 18% Metabolism and Nutrition Disorders Hypomagnesemia 28% 22% Hypophosphatemia 28% 21% Hyperkalemia 26% 19% Hyperglycemia 21% 15% Hyperlipidemia 18% 25% Hypokalemia 16% 18% Nervous System Disorders Tremor 34% 20% Headache 24% 25% Blood and Lymphatic System Disorders Anemia 30% 28% Leukopenia 16% 12% Miscellaneous Edema Peripheral 35% 46% Hypertension 32% 35% Insomnia 30% 21% Urinary Tract Infection 26% 22% Blood Creatinine Increased 23% 23% Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection "Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.” Liver Transplantation There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70); the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%), and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%), and Other (2%). The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12 month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation. The most common adverse reactions (≥ 38%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials. Table 7.
ssociated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials. Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus U.S. TRIAL EUROPEAN TRIAL Tacrolimus (N=250 ) Cyclosporine/AZA (N=250) Tacrolimus (N=264) Cyclosporine/AZA (N=265) Nervous System Headache 64% 60% 37% 26% Insomnia 64% 68% 32% 23% Tremor 56% 46% 48% 32% Paresthesia 40% 30% 17% 17% Gastrointestinal Diarrhea 72% 47% 37% 27% Nausea 46% 37% 32% 27% LFT Abnormal 36% 30% 6% 5% Anorexia 34% 24% 7% 5% Vomiting 27% 15% 14% 11% Constipation 24% 27% 23% 21% Cardiovascular Hypertension 47% 56% 38% 43% Urogenital Kidney Function Abnormal 40% 27% 36% 23% Creatinine Increased 39% 25% 24% 19% BUN Increased 30% 22% 12% 9% Oliguria 18% 15% 19% 12% Urinary Tract Infection 16% 18% 21% 19% Metabolic and Nutritional Hypomagnesemia 48% 45% 16% 9% Hyperglycemia 47% 38% 33% 22% Hyperkalemia 45% 26% 13% 9% Hypokalemia 29% 34% 13% 16% Hemic and Lymphatic Anemia 47% 38% 5% 1% Leukocytosis 32% 26% 8% 8% Thrombocytopenia 24% 20% 14% 19% Miscellaneous Pain 63% 57% 24% 22% Abdominal Pain 59% 54% 29% 22% Asthenia 52% 48% 11% 7% Fever 48% 56% 19% 22% Back Pain 30% 29% 17% 17% Ascites 27% 22% 7% 8% Peripheral Edema 26% 26% 12% 14% Respiratory System Pleural Effusion 30% 32% 36% 35% Dyspnea 29% 23% 5% 4% Atelectasis 28% 30% 5% 4% Skin and Appendages Pruritus 36% 20% 15% 7% Rash 24% 19% 10% 4% Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.” Heart Transplantation The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with tacrolimus (n=157) or cyclosporine (n=157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%). The most common adverse reactions (≥ 15%) observed in tacrolimus-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial. Adverse reactions in heart transplant patients in the European trial are presented below: Table 9.
ry tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial. Adverse reactions in heart transplant patients in the European trial are presented below: Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) Tacrolimus/AZA (N=157) Cyclosporine/AZA (N=157) Cardiovascular System Hypertension 62% 69% Pericardial Effusion 15% 14% Body as a Whole CMV Infection 32% 30% Infection 24% 21% Metabolic and Nutritional Disorders Diabetes Mellitus 26% 16% Hyperglycemia 23% 17% Hyperlipemia 18% 27% Hemic and Lymphatic System Anemia 50% 36% Leukopenia 48% 39% Urogenital System Kidney Function Abnormal 56% 57% Urinary Tract Infection 16% 12% Respiratory System Bronchitis 17% 18% NervousSystem Tremor 15% 6% In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and tacrolimus in combination with sirolimus (n=109), tacrolimus in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%). Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with tacrolimus and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin <10 g/dL) (65%), fasting blood glucose >140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs <3,000 cells/mcL (34%), serious bacterial infections (30%), magnesium <1.2 mEq/L (24%), platelet count <75,000 cells/mcL (19%), and other opportunistic infections (15%). Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.” New Onset Diabetes After Transplant Kidney Transplantation New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥126 mg/dL, HbA 1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies (14.1) ]. Table 10.
126 mg/dL, HbA 1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies (14.1) ]. Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2) Parameter Treatment Group Tacrolimus/MMF (N = 212) NEORAL/MMF (N = 212) NODAT 112/150 (75%) 93/152 (61%) Fasting Plasma Glucose ≥ 126 mg/dL 96/150 (64%) 80/152 (53%) HbA 1C ≥ 6% 59/150 (39%) 28/152 (18%) Insulin Use ≥ 30 days 9/150 (6%) 4/152 (3%) Oral Hypoglycemic Use 15/150 (10%) 5/152 (3%) In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of “use of insulin for 30 or more consecutive days with < 5 day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14. PTDM was reported in 20% of Tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 11). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12). Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA) Status of PTDM * Tacrolimus/AZA CsA/AZA Patients without pre-transplant history of diabetes mellitus 151 151 New onset PTDM * , 1 st Year 30/151 (20%) 6/151 (4%) Still insulin-dependent at one year in those without prior history of diabetes 25/151 (17%) 5/151 (3%) New onset PTDM * post 1 year 1 0 Patients with PTDM * at 2 years 16/151 (11%) 5/151 (3%) * Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial Patient Race Patients Who Developed PTDM * Tacrolimus Cyclosporine African-American 15/41 (37%) 3 (8%) Hispanic 5/17 (29%) 1 (6%) Caucasian 10/82 (12%) 1 (1%) Other 0/11 (0%) 1 (10%) Total 30/151 (20%) 6 (4%) * Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Liver Transplantation Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively, (Table 13). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1) ]. Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients Status of PTDM * U.S. Trial European Trial Tacrolimus Cyclosporine Tacrolimus Cyclosporine Patients at risk † 239 236 239 249 New Onset PTDM * 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) * Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
at risk † 239 236 239 249 New Onset PTDM * 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) * Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. † Patients without pre-transplant history of diabetes mellitus. Heart Transplantation Insulin-dependent PTDM was reported in 13% and 22% of tacrolimus-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 14). Hyperglycemia, defined as two fasting plasma glucose levels ≥126 mg/dL, was reported with the use of tacrolimus plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions ( 6.1 ) ]. Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients Status of PTDM * U.S. Trial European Trial Tacrolimus/ MMF Cyclosporine/MMF Tacrolimus/ AZA Cyclosporine/ AZA Patients at risk † 75 83 132 138 New Onset PTDM * 10 (13%) 6 (7%) 29 (22%) 5 (4%) Patients still on insulin at 1 year ‡ 7 (9%) 1 (1%) 24 (18%) 4 (3%) * Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. † Patients without pre-transplant history of diabetes mellitus. ‡ 7 to 12 months for the U.S. trial. Less Frequently Reported Adverse Reactions (>3% and <15%) in Liver, Kidney, and Heart Transplant Studies The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.
diabetes mellitus. ‡ 7 to 12 months for the U.S. trial. Less Frequently Reported Adverse Reactions (>3% and <15%) in Liver, Kidney, and Heart Transplant Studies The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials. Nervous System : Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired Special Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitus Gastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation Urogenital: Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis Metabolic/Nutritional: Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gain Endocrine: Cushing’s syndrome Hemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration Skin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweating • Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information 6.2 Postmarketing Experience The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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.
ing Experience The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug. Other reactions include: Cardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsades de pointes , venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia thrombotic microangiopathy Infections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; -polyoma virus-associated nephropathy (PVAN) including graft loss Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased Miscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) Nervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope Respiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis Special Senses: Blindness, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome
<table cellpadding="0pt" cellspacing="0pt" width="98%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/AZA (N=205)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/AZA (N=207)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content> Tremor Headache Insomnia Paresthesia Dizziness </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>54% 44% 32% 23% 19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34% 38% 30% 16% 16%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Diarrhea Nausea Constipation Vomiting Dyspepsia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>44% 38% 35% 29% 28%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>41% 36% 43% 23% 20%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hypertension Chest Pain </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>50% 19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>52% 13%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Creatinine Increased Urinary Tract Infection </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>45% 34%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42% 35%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hypophosphatemia Hypomagnesemia Hyperlipemia Hyperkalemia Diabetes Mellitus Hypokalemia Hyperglycemia Edema </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>49% 34% 31% 31% 24% 22% 22% 18%</paragraph></td><td align="center" styleCode="Rrule
="Lrule Botrule " valign="top"><paragraph>Hypophosphatemia Hypomagnesemia Hyperlipemia Hyperkalemia Diabetes Mellitus Hypokalemia Hyperglycemia Edema </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>49% 34% 31% 31% 24% 22% 22% 18%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>53% 17% 38% 32% 9% 25% 16% 19%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Anemia Leukopenia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>30% 15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24% 17%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Miscellaneous </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph>Infection </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph>45%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>49%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph>Peripheral Edema Asthenia Abdominal Pain Pain Fever Back Pain </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph>36% 34% 33% 32% 29% 24% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>48% 30% 31% 30% 29% 20% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Respiratory System </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph>Dyspnea Cough Increased </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph>22% 18% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>18% 15% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Musculoskeletal </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph>Arthralgia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph>25% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>24% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Skin </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph> </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="bottom"><paragraph>Rash Pruritus </paragraph></td><td align="center" styleCode="Botrule Lrule " valign="bottom"><paragraph>17% 15% </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="bo
Lrule Botrule " valign="bottom"><paragraph> </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="bottom"><paragraph>Rash Pruritus </paragraph></td><td align="center" styleCode="Botrule Lrule " valign="bottom"><paragraph>17% 15% </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="bo ttom"><paragraph>12% 7% </paragraph></td></tr></tbody></table>
Lrule Botrule " valign="bottom"><paragraph> </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="bottom"><paragraph>Rash Pruritus </paragraph></td><td align="center" styleCode="Botrule Lrule " valign="bottom"><paragraph>17% 15% </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="bo ttom"><paragraph>12% 7% </paragraph></td></tr></tbody></table> <table cellpadding="0pt" cellspacing="0pt" width="98%"><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" styleCode="Toprule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph> </paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">(Group C)</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">(Group A)</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">(Group B)</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph> </paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">(N=403)</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">(N=384)</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">(N=408)</content></paragraph></td></tr><tr><td valign="top"><paragraph>Diarrhea </paragraph></td><td align="center" valign="top"><paragraph>25%</paragraph></td><td align="center" valign="top"><paragraph>16%</paragraph></td><td align="center" valign="top"><paragraph>13%</paragraph></td></tr><tr><td valign="top"><paragraph>Urinary Tract Infection </paragraph></td><td align="center" valign="top"><paragraph>24%</paragraph></td><td align="center" valign="top"><paragraph>28%</paragraph></td><td align="center" valign="top"><paragraph>24%</paragraph></td></tr><tr><td valign="top"><paragraph>Anemia </paragraph></td><td align="center" valign="top"><paragraph>17%</paragraph></td><td align="center" valign="top"><paragraph>19%</paragraph></td><td align="center" valign="top"><paragraph>17%</paragraph></td></tr><tr><td valign="top"><paragraph>Hypertension </paragraph></td><td align="center" valign="top"><paragraph>13%</paragraph></td><td align="center" valign="top"><paragraph>14%</paragraph></td><td align="center" valign="top"><paragraph>12%</paragraph></td></tr><tr><td valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" valign="top"><paragraph>13%</paragraph></td><td align="center" valign="top"><paragraph>10%</paragraph></td><td align="center" valign="top"><paragraph>10%</paragraph></td></tr><tr><td valign="top"><paragraph>Edema Peripheral </paragraph></td><td align="center" valign="top"><paragraph>11%</paragraph></td><td align="center" valign="top"><paragraph>12%</paragraph></td><td align="center" valign="top"><paragraph>13%</paragraph></td></tr><tr><td valign="top"><paragraph>Hyperlipidemia </paragraph></td><td align="center" valign="top"><paragraph>10%</paragraph></td><td align="center" valign="top"><paragraph>15%</paragraph></td><td align="center" valign="top"><paragraph>13%</paragraph></td></tr><tr><td colspan="4" styleCode="Botrule " valign="top"><paragraph>Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil </paragraph></td></tr></tbody></table>
valign="top"><paragraph>13%</paragraph></td></tr><tr><td colspan="4" styleCode="Botrule " valign="top"><paragraph>Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil </paragraph></td></tr></tbody></table> <table cellpadding="0pt" cellspacing="0pt" width="98%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/MMF </content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/MMF </content></paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">(N=212) </content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">(N=212) </content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders </content></paragraph></td><td styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Diarrhea </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>44% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Nausea </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>39% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 36% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>41% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Vomiting </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>26% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Dyspepsia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>18% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Injury, Poisoning, and Procedural Complications </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Post-Procedural Pain </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>29% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Incision Site Complication </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>28% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23% </paragraph></
graph>27% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Incision Site Complication </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>28% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23% </paragraph></ td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Graft Dysfunction </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>24% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hypomagnesemia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>28% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hypophosphatemia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>28% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hyperkalemia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>26% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hyperglycemia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>21% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hyperlipidemia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>18% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hypokalemia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>16% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Tremor </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>34% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Headache </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>24% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Blood and Lymphatic System Disorders </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule
aph>25% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Blood and Lymphatic System Disorders </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Anemia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>30% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 16% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Miscellaneous </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Edema Peripheral </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>35% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>46% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hypertension </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>32% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Insomnia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>30% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Urinary Tract Infection </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>26% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22% </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Blood Creatinine Increased </paragraph></td><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>23% </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>23% </paragraph></td></tr></tbody></table>
td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Blood Creatinine Increased </paragraph></td><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>23% </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>23% </paragraph></td></tr></tbody></table> <table width="100%"><col width="20%"/><col width="14%"/><col width="19%"/><col width="14%"/><col width="33%"/><tbody><tr><td align="center" rowspan="4" styleCode="Botrule Lrule Toprule " valign="top"><paragraph> </paragraph></td><td align="center" colspan="2" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">U.S.
h="20%"/><col width="14%"/><col width="19%"/><col width="14%"/><col width="33%"/><tbody><tr><td align="center" rowspan="4" styleCode="Botrule Lrule Toprule " valign="top"><paragraph> </paragraph></td><td align="center" colspan="2" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">U.S. TRIAL</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">EUROPEAN TRIAL</content></paragraph></td></tr><tr><td align="center" rowspan="3" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus</content> <content styleCode="bold">(N=250</content>) </paragraph></td><td align="center" rowspan="3" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N=250)</content></paragraph></td><td align="center" rowspan="3" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus</content> <content styleCode="bold">(N=264)</content> </paragraph></td><td align="center" rowspan="1" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N=265)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Headache </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>64%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>60%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Insomnia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>64%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>68%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Tremor </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>46%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Paresthesia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>40%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " va
d><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " va lign="top"><paragraph><content styleCode="bold">Gastrointestinal </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Diarrhea </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>72%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Nausea </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>46%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">LFT Abnormal</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Anorexia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Vomiting </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Constipation </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"
align="top"><paragraph>21%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top" ><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hypertension </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>43%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Kidney Function Abnormal </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>40%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Creatinine Increased </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>39%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>BUN Increased </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Oliguria </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Urinary Tract Infection </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>21%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td sty
ragraph>16%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>21%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td sty leCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hypomagnesemia</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hyperglycemia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>33%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hyperkalemia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>45%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hypokalemia</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>34%</paragraph></td><td styleCode="Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Anemia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Leukocytosis</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>26%</pa
Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Leukocytosis</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>26%</pa ragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Thrombocytopenia</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Miscellaneous</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Pain </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>63%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>57%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Abdominal Pain </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>59%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>54%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Asthenia </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>52%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Fever </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>48%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Back Pain </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Ascites <
"Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Ascites < /paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>22%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Peripheral Edema</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Pleural Effusion </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>32%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Dyspnea </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>29%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Atelectasis</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>30%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and Appendages</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Pruritus </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCo
graph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Pruritus </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCo de="Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Rash </paragraph></td><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table>
aph>24%</paragraph></td><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table> <table width="100%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/AZA </content> <content styleCode="bold">(N=157)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N=157)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular System</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hypertension </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>62% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>69%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Pericardial Effusion </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>15% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Body as a Whole </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>CMV Infection </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>32% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Infection </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>24% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>21%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders </content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Diabetes Mellitus </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>26% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>16%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hyperglycemia </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>23% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Hyperlipemia </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>18% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic System </content></paragraph></td><td ali
ign="center" styleCode="Botrule " valign="top"><paragraph>18% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hemic and Lymphatic System </content></paragraph></td><td ali gn="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="middle"><paragraph>Anemia </paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>50% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>36%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> 48% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>39%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Urogenital System </paragraph></td><td styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Kidney Function Abnormal </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>56% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>57%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Urinary Tract Infection </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>16% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory System</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Bronchitis </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>17% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NervousSystem</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Tremor </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>15% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr></tbody></table>
n="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Tremor </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>15% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr></tbody></table> <table cellpadding="0pt" cellspacing="0pt" width="98%"><col width="33%"/><col width="34%"/><col width="33%"/><tbody><tr><td align="center" rowspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Parameter</content></paragraph></td><td align="center" colspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold"> Treatment Group </content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Tacrolimus/MMF</content> <content styleCode="bold">(N = 212)</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">NEORAL/MMF</content> <content styleCode="bold">(N = 212)</content></paragraph></td></tr><tr><td valign="top"><paragraph>NODAT </paragraph></td><td align="center" valign="top"><paragraph>112/150 (75%) </paragraph></td><td align="center" valign="top"><paragraph>93/152 (61%) </paragraph></td></tr><tr><td valign="top"><paragraph>Fasting Plasma Glucose ≥ 126 mg/dL </paragraph></td><td align="center" valign="top"><paragraph>96/150 (64%) </paragraph></td><td align="center" valign="top"><paragraph>80/152 (53%) </paragraph></td></tr><tr><td valign="top"><paragraph>HbA<sub>1C </sub>≥ 6% </paragraph></td><td align="center" valign="top"><paragraph>59/150 (39%) </paragraph></td><td align="center" valign="top"><paragraph>28/152 (18%) </paragraph></td></tr><tr><td valign="top"><paragraph>Insulin Use ≥ 30 days </paragraph></td><td align="center" valign="top"><paragraph>9/150 (6%) </paragraph></td><td align="center" valign="top"><paragraph>4/152 (3%) </paragraph></td></tr><tr><td styleCode="Botrule " valign="bottom"><paragraph>Oral Hypoglycemic Use </paragraph></td><td align="center" styleCode="Botrule " valign="bottom"><paragraph>15/150 (10%) </paragraph></td><td align="center" styleCode="Botrule " valign="bottom"><paragraph>5/152 (3%) </paragraph></td></tr></tbody></table>
h></td></tr><tr><td styleCode="Botrule " valign="bottom"><paragraph>Oral Hypoglycemic Use </paragraph></td><td align="center" styleCode="Botrule " valign="bottom"><paragraph>15/150 (10%) </paragraph></td><td align="center" styleCode="Botrule " valign="bottom"><paragraph>5/152 (3%) </paragraph></td></tr></tbody></table> <table cellpadding="0pt" cellspacing="0pt" width="98%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Status of PTDM</content><sup>*</sup></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/AZA</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">CsA/AZA</content></paragraph></td></tr><tr><td valign="top"><paragraph>Patients without pre-transplant history of diabetes mellitus</paragraph></td><td align="center" valign="top"><paragraph>151</paragraph></td><td align="center" valign="top"><paragraph>151</paragraph></td></tr><tr><td valign="top"><paragraph>New onset PTDM<sup>*</sup>, 1<sup>st</sup> Year </paragraph></td><td align="center" valign="top"><paragraph>30/151 (20%)</paragraph></td><td align="center" valign="top"><paragraph>6/151 (4%)</paragraph></td></tr><tr><td valign="top"><paragraph>Still insulin-dependent at one year in those without prior history of diabetes</paragraph></td><td align="center" valign="top"><paragraph>25/151 (17%)</paragraph></td><td align="center" valign="top"><paragraph>5/151 (3%)</paragraph></td></tr><tr><td valign="top"><paragraph>New onset PTDM<sup>* </sup>post 1 year </paragraph></td><td align="center" valign="top"><paragraph>1</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Patients with PTDM<sup>* </sup> at 2 years </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>16/151 (11%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>5/151 (3%)</paragraph></td></tr></tbody></table>
r><tr><td styleCode="Botrule " valign="top"><paragraph>Patients with PTDM<sup>* </sup> at 2 years </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>16/151 (11%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>5/151 (3%)</paragraph></td></tr></tbody></table> <table cellpadding="0pt" cellspacing="0pt" width="98%"><col width="33%"/><col width="33%"/><col width="34%"/><tbody><tr><td rowspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Patient Race </content></paragraph></td><td align="center" colspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Patients Who Developed PTDM<sup>*</sup></content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Tacrolimus</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Cyclosporine</content></paragraph></td></tr><tr><td valign="top"><paragraph>African-American</paragraph></td><td align="center" valign="top"><paragraph>15/41 (37%)</paragraph></td><td align="center" valign="top"><paragraph>3 (8%)</paragraph></td></tr><tr><td valign="top"><paragraph>Hispanic </paragraph></td><td align="center" valign="top"><paragraph>5/17 (29%)</paragraph></td><td align="center" valign="top"><paragraph>1 (6%)</paragraph></td></tr><tr><td valign="top"><paragraph>Caucasian </paragraph></td><td align="center" valign="top"><paragraph>10/82 (12%)</paragraph></td><td align="center" valign="top"><paragraph>1 (1%)</paragraph></td></tr><tr><td valign="top"><paragraph>Other </paragraph></td><td align="center" valign="top"><paragraph>0/11 (0%)</paragraph></td><td align="center" valign="top"><paragraph>1 (10%)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Total </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>30/151 (20%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6 (4%)</paragraph></td></tr></tbody></table>
p"><paragraph>1 (10%)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Total </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>30/151 (20%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6 (4%)</paragraph></td></tr></tbody></table> <table cellpadding="0pt" cellspacing="0pt" width="98%"><col width="23%"/><col width="19%"/><col width="19%"/><col width="19%"/><col width="19%"/><tbody><tr><td rowspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Status of PTDM</content>* </paragraph></td><td align="center" colspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">U.S. Trial </content></paragraph></td><td align="center" colspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">European Trial </content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Tacrolimus</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Cyclosporine</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Tacrolimus</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Cyclosporine</content></paragraph></td></tr><tr><td valign="top"><paragraph>Patients at risk<sup>†</sup></paragraph></td><td align="center" valign="top"><paragraph>239</paragraph></td><td align="center" valign="top"><paragraph>236</paragraph></td><td align="center" valign="top"><paragraph>239</paragraph></td><td align="center" valign="top"><paragraph>249</paragraph></td></tr><tr><td valign="top"><paragraph>New Onset PTDM<sup>*</sup></paragraph></td><td align="center" valign="top"><paragraph>42 (18%)</paragraph></td><td align="center" valign="top"><paragraph>30 (13%)</paragraph></td><td align="center" valign="top"><paragraph>26 (11%)</paragraph></td><td align="center" valign="top"><paragraph>12 (5%)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Patients still on insulin at 1 year</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>23 (10%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>19 (8%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>18 (8%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6 (2%)</paragraph></td></tr></tbody></table>
<paragraph>23 (10%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>19 (8%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>18 (8%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6 (2%)</paragraph></td></tr></tbody></table> <table width="100%"><col width="29%"/><col width="17%"/><col width="19%"/><col width="17%"/><col width="17%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Status of PTDM<sup>*</sup></content></paragraph></td><td align="center" colspan="2" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">U.S. Trial </content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">European Trial </content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/ MMF</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/MMF </content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/ AZA </content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/ AZA </content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Patients at risk<sup>†</sup></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>75</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> 83 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>132 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>138 </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>New Onset PTDM<sup>*</sup></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>10 (13%) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6 (7%) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>29 (22%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5 (4%) </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Patients still on insulin at 1 year <sup>‡</sup></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>7 (9%) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1 (1%) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>24 (18%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4 (3%) </paragraph></td></tr></tbody></table>
7 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 * Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juice † 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 ‡ : 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 ‡ : 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 to 3 days and continue monitoring as necessary [see Warnings and Precautions ( 5.11 )].
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 to 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 capsules dose if needed [see Dosage and Administration ( 2.2 , 2.6 )]. * Tacrolimus 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. † High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor. ‡ 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). 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 ta crolimus is co-administered with cannabidiol [see Dosage and Administration ( 2.2 , 2.6 )and Warnings and Precautions ( 5.17 )].
<table width="100%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Drug/Substance Class or Name </content></paragraph></td><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Drug Interaction Effect</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Recommendations</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Grapefruit or grapefruit juice<sup>†</sup></paragraph></td><td styleCode="Lrule Botrule " valign="top"><paragraph> May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#_6c58d880-0731-32f6-fc2f-48b62ea0f34c">5.6</linkHtml>, <linkHtml href="#_dc63967f-8dce-04c0-f4a6-b5609d0483f7">5.11</linkHtml>, <linkHtml href="#_27aa2a64-7011-ee51-8b2a-d5252cbe81a2">5.12</linkHtml>)]</content>. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Avoid grapefruit or grapefruit juice. </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Strong CYP3A Inducers<sup>‡</sup>: Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s Wort </paragraph></td><td styleCode="Lrule Botrule " valign="top"><paragraph> May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#_dc63967f-8dce-04c0-f4a6-b5609d0483f7">5.11</linkHtml>)]. </content> </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations [see <content styleCode="italics">Dosage and Administration</content> (<linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">2.2</linkHtml><linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">,</linkHtml><linkHtml href="#_4c11e474-0cf1-738d-70b3-aad07f9c206c">2.6</linkHtml>) and <content styleCode="italics">Clinical Pharmacology</content> (<linkHtml href="#PHARMACOKINETICS">12.3</linkHtml>)]. </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Strong CYP3A Inhibitors<sup>‡</sup>: Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, <content styleCode="italics">Schisandra sphenanthera</content> extracts </paragraph></td><td styleCode="Lrule Botrule " valign="top"><paragraph> 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 <content styleCode="italics">[see Warnings and Precautions(<linkHtml href="#_6c58d880-0731-32f6-fc2f-48b62ea0f34c">5.6</linkHtml>, <linkHtml href="#_dc63967f-8dce-04c0-f4a6-b5609d0483f7">5.11,</linkHtml><linkHtml href="#_27aa2a64-7011-ee51-8b2a-d5252cbe81a2">5.12</linkHtml>)]</content>.
ate reduction of tacrolimus dose <content styleCode="italics">[see Warnings and Precautions(<linkHtml href="#_6c58d880-0731-32f6-fc2f-48b62ea0f34c">5.6</linkHtml>, <linkHtml href="#_dc63967f-8dce-04c0-f4a6-b5609d0483f7">5.11,</linkHtml><linkHtml href="#_27aa2a64-7011-ee51-8b2a-d5252cbe81a2">5.12</linkHtml>)]</content>. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> 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 <content styleCode="italics">Dosage and Administration</content> (<linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">2.2</linkHtml><linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">,</linkHtml><linkHtml href="#_4c11e474-0cf1-738d-70b3-aad07f9c206c"> 2.6</linkHtml>) and <content styleCode="italics">Clinical Pharmacology</content> (<linkHtml href="#PHARMACOKINETICS">12.3</linkHtml>)]. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1 to 3 days and continue monitoring as necessary [see Warnings and Precautions (<linkHtml href="#_dc63967f-8dce-04c0-f4a6-b5609d0483f7">5.11</linkHtml>)]. </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> 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 </paragraph></td><td styleCode="Lrule Botrule " valign="top"><paragraph> May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see <content styleCode="italics">Warnings and Precautions</content> (<linkHtml href="#_6c58d880-0731-32f6-fc2f-48b62ea0f34c">5.6</linkHtml>, <linkHtml href="#_dc63967f-8dce-04c0-f4a6-b5609d0483f7">5.11</linkHtml>, <linkHtml href="#_27aa2a64-7011-ee51-8b2a-d5252cbe81a2">5.12</linkHtml>)]. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see <content styleCode="italics">Dosage and Administration</content> (<linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">2.2</linkHtml><linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">,</linkHtml><linkHtml href="#_4c11e474-0cf1-738d-70b3-aad07f9c206c"> 2.6</linkHtml>) and <content styleCode="italics">Clinical Pharmacology</content> (<linkHtml href="#PHARMACOKINETICS">12.3</linkHtml>)]. </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide </paragraph></td><td styleCode="Lrule Botrule " valign="top"><paragraph> May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see Warnings and Precautions</content> (<linkHtml href="#_6c58d880-0731-32f6-fc2f-48b62ea0f34c">5.6</linkHtml>, <linkHtml href="#_dc63967f-8dce-04c0-f4a6-b5609d0483f7">5.11</linkHtml>, <linkHtml href="#_27aa2a64-7011-ee51-8b2a-d5252cbe81a2">5.12</linkHtml>)].
eurotoxicity, QT prolongation) <content styleCode="italics">[see Warnings and Precautions</content> (<linkHtml href="#_6c58d880-0731-32f6-fc2f-48b62ea0f34c">5.6</linkHtml>, <linkHtml href="#_dc63967f-8dce-04c0-f4a6-b5609d0483f7">5.11</linkHtml>, <linkHtml href="#_27aa2a64-7011-ee51-8b2a-d5252cbe81a2">5.12</linkHtml>)]. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed<content styleCode="italics"> [see Dosage and Administration</content> (<linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">2.2</linkHtml><linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">,</linkHtml><linkHtml href="#_4c11e474-0cf1-738d-70b3-aad07f9c206c"> 2.6</linkHtml>) and <content styleCode="italics">Clinical Pharmacology (<linkHtml href="#PHARMACOKINETICS">12.3</linkHtml>)</content>]. </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone </paragraph></td><td styleCode="Lrule Botrule " valign="top"><paragraph> May decrease tacrolimus whole blood trough concentrations. </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed <content styleCode="italics">[see Dosage and Administration</content> (<linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">2.2</linkHtml><linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">,</linkHtml><linkHtml href="#_4c11e474-0cf1-738d-70b3-aad07f9c206c"> 2.6</linkHtml>)].</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Caspofungin </paragraph></td><td styleCode="Botrule Lrule " valign="top"><paragraph>May decrease tacrolimus whole blood trough concentrations. </paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus capsules dose if needed [see Dosage and Administration (<linkHtml href="#_a17eaea8-2b11-5d5e-1a25-2c8fd5dd78b4">2.2</linkHtml>, <linkHtml href="#_4c11e474-0cf1-738d-70b3-aad07f9c206c">2.6</linkHtml>)]. </paragraph></td></tr></tbody></table>
8 USE IN SPECIFIC POPULATIONS Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. ( 8.1 , 8.3 ) Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to tacrolimus 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data] . The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death. Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population.
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 Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions (5.4) ]. Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions ( 5.7 , 5.8 )]. 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 tacrolimus. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus. 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 16. 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 renal 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 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus Kidney Liver Pregnancy Outcomes* 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%† 5% * Includes multiple births and terminations. † Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. 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 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed.
kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), 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 to 6.9 times the recommended clinical dose range) 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 to 6.9 times the recommended clinical dose range); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1 mg/kg (0.8 to 2.2 times the recommended clinical dose range). 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 to 6.9 times the 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 to 2.2 times the recommended clinical dose range) [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 [seeUse in Specific Populations ( 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 tacrolimus and any potential adverse effects on the breastfed child from tacrolimus or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Tacrolimus 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 tacrolimus [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 tacrolimus [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use Safety and effectiveness have been established in pediatric liver transplant patients. Liver Transplantation Safety and efficacy in pediatric de novo liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation.
c de novo liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients[see Dosage and Administration (2.3) , Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3) and Clinical Studies ( 14.2 )]. Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 8.5 Geriatric Use Clinical trials of tacrolimus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 volunteers with normal renal function. However, consideration should be given to dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration ( 2.4 ) 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 volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology ( 12.3 )]. The use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )]. 8.8 Race or Ethnicity African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]. 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 ( 5.4 )].
<table width="100%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Kidney</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Liver</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Pregnancy Outcomes* </content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">462</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">253</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Miscarriage </content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> 24.5% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> 25% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Live births </content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">331</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">180</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Pre-term delivery (< 37 weeks) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> 49% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> 42% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Low birth weight (< 2500 g) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> 42% </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> 30% </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph> Birth defects </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> 8%† </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> 5% </paragraph></td></tr></tbody></table>
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to tacrolimus 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data] . The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death. Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported. Maternal Adverse Reactions Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions (5.4) ]. Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia.
ng were reported. Maternal Adverse Reactions Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions (5.4) ]. Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions ( 5.7 , 5.8 )]. 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 tacrolimus. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus. 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 16. 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 renal 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 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus Kidney Liver Pregnancy Outcomes* 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%† 5% * Includes multiple births and terminations. † Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. 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 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), 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 to 6.9 times the recommended clinical dose range) 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.
o 6.9 times the recommended clinical dose range) 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 to 6.9 times the recommended clinical dose range); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1 mg/kg (0.8 to 2.2 times the recommended clinical dose range). 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 to 6.9 times the 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 to 2.2 times the recommended clinical dose range) [see Nonclinical Toxicology ( 13.1 )].
8.3 Females and Males of Reproductive Potential Contraception Tacrolimus 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 tacrolimus [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 tacrolimus [see Nonclinical Toxicology ( 13.1 )].
8.4 Pediatric Use Safety and effectiveness have been established in pediatric liver transplant patients. Liver Transplantation Safety and efficacy in pediatric de novo liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients[see Dosage and Administration (2.3) , Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3) and Clinical Studies ( 14.2 )]. Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
10 OVERDOSAGE Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of tacrolimus [see Adverse Reactions ( 6.1 , 6.2 )] including tremors, abnormal renal function, hypertension, and peripheral edema; in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
11 DESCRIPTION Tacrolimus USP, previously known as FK506, is the active ingredient in tacrolimus capsules USP. Tacrolimus USP is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis . Chemically, tacrolimus USP is designated as [3S-[3R*[E(1S*,3S*,4S*)], 4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate. The chemical structure of tacrolimus is: Tacrolimus USP has an molecular formula of C 44 H 69 NO 12 •H 2 O and a formula weight of 822.03. Tacrolimus USP appears as white to off white granular powder. It is practically insoluble in water, freely soluble in methanol, ethanol, acetone, ehyl acetate, chloroform. Tacrolimus USP is available for oral administration as capsules containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus, USP. Inactive ingredients include croscarmellose sodium, lactose monohydrate and magnesium stearate. The 0.5 mg capsule shell contains gelatin, iron oxide red, iron oxide yellow and titanium dioxide, the 1 mg capsule shell contains gelatin and titanium dioxide and the 5 mg capsule shell contains gelatin, iron oxide red, iron oxide black, and titanium dioxide. Tacrolimus Capsules meets USP Organic Impurities Test Procedure 2. structure
12 CLINICAL PHARMACOLOGY 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, 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 Population N Route(Dose) Parameters C max (ng/mL) T max (hr) AUC (ng•hr/mL) t 1/2 (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 to 6] # 82.7 Þ ± 63.2 * ‡ ‡ 14 PO(0.15 mg/kg/day) ¶ 24.5 ±13.7 1.5 [0.4 to 4] # 142 Þ ± 116 * ‡ ‡ * Not applicable † AUC 0-inf ‡ Not available § AUC 0-t ¶ Determined after the first dose # Median [range] Þ AUC 0-12 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.
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 (C max ) 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 (C min ) 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 C max were decreased 37% and 77%, respectively; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max 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 C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C max 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 C max (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 (CYP3A 4 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.
roposed. 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 PediatricPatients Tacrolimus capsules Pharmacokinetics in Pediatric Patients Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5±3.8 hours, 2.6±2.1 L/kg and 0.138±0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C max were 337±167 ng·hr/mL and 48.4±27.9 ng/mL, respectively. The absolute bioavailability was 31±24%. Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2±2.4 years of age. Following IV infusion of a 0.06 mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2±5 hours and 0.12±0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and C max were 181±65 ng·hr/mL and 30±11 ng/mL, respectively. The absolute bioavailability was 19±14%. Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration ( 2.3 ) ]. Renal and Hepatic Impaired Patients The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19. Table 19. Pharmacokinetic in Renal and Hepatic Impaired Adult Patients Population (No.
e Dosage and Administration ( 2.3 ) ]. Renal and Hepatic Impaired Patients The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19. Table 19. Pharmacokinetic in Renal and Hepatic Impaired Adult Patients Population (No. of Patients) Dose AUC 0-t (ng·hr/mL) t 1/2 (hr) V(L/kg) CI(L/hr/kg) Renal Impairment (n=12) 0.02 mg/kg/4 hr IV 393±123 (t=60 hr) 26.3 ±9.2 1.07±0.20 0.038±0.014 Mild Hepatic Impairment (n=6) 0.02 mg/kg/4 hr IV 367±107 (t=72 hr) 60.6±43.8 Range: 27.8 to 141 3.1±1.6 0.042±0.02 7.7 mg PO 488±320 (t=72 hr) 66.1±44.8 Range: 29.5 to 138 3.7±4.7 * 0.034±0.019 * Severe Hepatic Impairment (n=6, IV) 0.02 mg/kg/4 hr IV (n=2) 0.01 mg/kg/8 hr IV (n=4) 762±204 (t=120 hr) 289±117 (t=144 hr) 198±158 Range: 81 to 436 3.9±1.0 0.017±0.013 (n=5, PO) † 8 mg PO (n=1)5 mg PO (n=4) 4 mg PO (n=1) 658 (t=120 hr)533±156 (t=144 hr) 119±35 Range: 85 to 178 3.1±3.4* 0.016±0.011 * * Corrected for bioavailability † 1 patient did not receive the PO dose Patients with Renal Impairment Tacrolimus pharmacokinetics, following a single IV administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3. 9 ± 1.6 and 12 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 19) [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )]. Patients with Hepatic Impairment Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: >10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [ see Dosage and Administration ( 2.5 ) and Use in Specific Populations (8.7) ]. Patients with Cystic Fibrosis Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration ( 2.2 , 2.3 )] . Racial or Ethnic Groups The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of tacrolimus to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (±SD) tacrolimus C max in African-Americans (23.6±12.1 ng/mL) was significantly lower than in Caucasians (40.2±12.6 ng/mL) and the Latino-Americans (36.2±15.8 ng/mL) (p<0.01). Mean AUC 0-inf tended to be lower in African-Americans (203±115 ng·hr/mL) than Caucasians (344±186 ng·hr/mL) and the Latino- Americans (274±150 ng·hr/mL). The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was significantly lower than in Caucasians (19±5.8%, p=0.011). There was no significant difference in mean terminal T 1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration ( 2.2 ) ].
1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration ( 2.2 ) ]. Male and Female Patients A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences. 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 and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus C max relative to tacrolimus administration alone [see Drug Interactions ( 7.2 • )].Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions ( 7.2 )]. • Voriconazole (see complete prescribing information for VFEND): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUC τ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions ( 7.2 )].
eat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUC τ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions ( 7.2 )]. • Posaconazole (see complete prescribing information for Noxafil): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) C max and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions ( 7.2 )] . • Caspofungin (see complete prescribing information for CANCIDAS): Caspofungin reduced the blood AUC 0-12 of tacrolimus by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions ( 7.2 )]. The mechanism of interaction has not been confirmed. Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
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 Population N Route(Dose) Parameters C max (ng/mL) T max (hr) AUC (ng•hr/mL) t 1/2 (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 to 6] # 82.7 Þ ± 63.2 * ‡ ‡ 14 PO(0.15 mg/kg/day) ¶ 24.5 ±13.7 1.5 [0.4 to 4] # 142 Þ ± 116 * ‡ ‡ * Not applicable † AUC 0-inf ‡ Not available § AUC 0-t ¶ Determined after the first dose # Median [range] Þ AUC 0-12 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 (C max ) 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 (C min ) 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.
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 C max were decreased 37% and 77%, respectively; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max 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 C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C max 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 C max (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 (CYP3A 4 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.
.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 PediatricPatients Tacrolimus capsules Pharmacokinetics in Pediatric Patients Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5±3.8 hours, 2.6±2.1 L/kg and 0.138±0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C max were 337±167 ng·hr/mL and 48.4±27.9 ng/mL, respectively. The absolute bioavailability was 31±24%. Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2±2.4 years of age. Following IV infusion of a 0.06 mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2±5 hours and 0.12±0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and C max were 181±65 ng·hr/mL and 30±11 ng/mL, respectively. The absolute bioavailability was 19±14%. Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration ( 2.3 ) ]. Renal and Hepatic Impaired Patients The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19. Table 19. Pharmacokinetic in Renal and Hepatic Impaired Adult Patients Population (No. of Patients) Dose AUC 0-t (ng·hr/mL) t 1/2 (hr) V(L/kg) CI(L/hr/kg) Renal Impairment (n=12) 0.02 mg/kg/4 hr IV 393±123 (t=60 hr) 26.3 ±9.2 1.07±0.20 0.038±0.014 Mild Hepatic Impairment (n=6) 0.02 mg/kg/4 hr IV 367±107 (t=72 hr) 60.6±43.8 Range: 27.8 to 141 3.1±1.6 0.042±0.02 7.7 mg PO 488±320 (t=72 hr) 66.1±44.8 Range: 29.5 to 138 3.7±4.7 * 0.034±0.019 * Severe Hepatic Impairment (n=6, IV) 0.02 mg/kg/4 hr IV (n=2) 0.01 mg/kg/8 hr IV (n=4) 762±204 (t=120 hr) 289±117 (t=144 hr) 198±158 Range: 81 to 436 3.9±1.0 0.017±0.013 (n=5, PO) † 8 mg PO (n=1)5 mg PO (n=4) 4 mg PO (n=1) 658 (t=120 hr)533±156 (t=144 hr) 119±35 Range: 85 to 178 3.1±3.4* 0.016±0.011 * * Corrected for bioavailability † 1 patient did not receive the PO dose Patients with Renal Impairment Tacrolimus pharmacokinetics, following a single IV administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3. 9 ± 1.6 and 12 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 19) [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )]. Patients with Hepatic Impairment Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: >10).
.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: >10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [ see Dosage and Administration ( 2.5 ) and Use in Specific Populations (8.7) ]. Patients with Cystic Fibrosis Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration ( 2.2 , 2.3 )] . Racial or Ethnic Groups The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of tacrolimus to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (±SD) tacrolimus C max in African-Americans (23.6±12.1 ng/mL) was significantly lower than in Caucasians (40.2±12.6 ng/mL) and the Latino-Americans (36.2±15.8 ng/mL) (p<0.01). Mean AUC 0-inf tended to be lower in African-Americans (203±115 ng·hr/mL) than Caucasians (344±186 ng·hr/mL) and the Latino- Americans (274±150 ng·hr/mL). The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was significantly lower than in Caucasians (19±5.8%, p=0.011). There was no significant difference in mean terminal T 1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration ( 2.2 ) ]. Male and Female Patients A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences. 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.
in 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 and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus C max relative to tacrolimus administration alone [see Drug Interactions ( 7.2 • )].Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions ( 7.2 )]. • Voriconazole (see complete prescribing information for VFEND): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUC τ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions ( 7.2 )]. • Posaconazole (see complete prescribing information for Noxafil): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) C max and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions ( 7.2 )] . • Caspofungin (see complete prescribing information for CANCIDAS): Caspofungin reduced the blood AUC 0-12 of tacrolimus by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions ( 7.2 )]. The mechanism of interaction has not been confirmed. Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
<table width="100%"><col width="14%"/><col width="9%"/><col width="15%"/><col width="11%"/><col width="8%"/><col width="12%"/><col width="10%"/><col width="11%"/><col width="9%"/><thead><tr><th align="left" rowspan="2" styleCode="Botrule Lrule Toprule " valign="top"><content styleCode="bold">Population </content></th><th align="center" rowspan="2" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">N </content></th><th align="center" rowspan="2" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">Route(Dose)</content></th><th align="center" colspan="6" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Parameters</content></th></tr><tr><th align="center" styleCode="Lrule Botrule " valign="top"><content styleCode="bold">C<sub>max</sub> (ng/mL)</content></th><th align="center" styleCode="Botrule " valign="top"><content styleCode="bold">T<sub>max</sub> (hr)</content></th><th align="center" styleCode="Botrule " valign="top"><content styleCode="bold">AUC (ng•hr/mL)</content></th><th align="center" styleCode="Botrule " valign="top"><content styleCode="bold">t<sub>1/2</sub> (hr)</content></th><th align="center" styleCode="Botrule " valign="top"><content styleCode="bold">CL (L/hr/kg)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">V (L/kg)</content></th></tr></thead><tbody><tr><td align="center" rowspan="2" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Healthy Volunteers</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>IV (0.025 mg/kg/4 hr)</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>652<sup>†</sup> ± 156</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>34.2 ± 7.7</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>0.040 ± 0.009</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>1.91 ± 0.31</paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>PO(5 mg) (capsules)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>28.8 ± 8.9</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.5 ± 0.7</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>266<sup>† </sup>± 95</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>32.3 ± 8.8</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>‡</paragraph></td></tr><tr><td align="center" rowspan="3" styleCode="Lrule Botrule " valign="top"><paragraph>Kidney Transplant Patients</paragraph></td><td align="center" rowspan="3" styleCode="Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>IV(0.02 mg/kg/12 hr)</paragraph></td><td align="center" styleCode="Botrul
ode="Lrule Botrule " valign="top"><paragraph>Kidney Transplant Patients</paragraph></td><td align="center" rowspan="3" styleCode="Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>IV(0.02 mg/kg/12 hr)</paragraph></td><td align="center" styleCode="Botrul e " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>294<sup>†</sup> ± 262</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>18.8 ± 16.7</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.083 ± 0.050</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> 1.41 ± 0.66</paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>PO(0.2 mg/kg/day)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>19.2 ± 10.3</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>203<sup>† </sup>± 42</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>‡</paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>PO(0.3 mg/kg/day)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>24.2 ± 15.8</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.5</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>288<sup>†</sup> ± 93</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>‡</paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Lrule Botrule " valign="top"><paragraph>Liver Transplant Patients</paragraph></td><td align="center" rowspan="2" styleCode="Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>IV(0.05 mg/kg/12 hr)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>3300<sup>†</sup> ± 2130</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> 11.7 ± 3.9</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.053 ± 0.017</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> 0.85 ± 0.30</paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>PO(0.3 mg/kg/day)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>68.5 ± 30</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2.3 ± 1.5</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>519<sup>†</sup> ± 179</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>‡</paragraph></td><
sup>†</sup> ± 179</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>‡</paragraph></td>< /tr><tr><td align="center" rowspan="3" styleCode="Lrule Botrule " valign="top"><paragraph>Heart Transplant Patients</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>IV (0.01 mg/kg/day as a continuous infusion)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>954<sup>§</sup> ± 334</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>23.6 ± 9.22</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.051 ± 0.015</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>‡</paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>PO(0.075 mg/kg/day)<sup>¶</sup></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> 14.7 ± 7.79</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2.1 [0.5 to 6]<sup>#</sup></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>82.7<sup>Þ</sup> ± 63.2</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>‡</paragraph></td></tr><tr><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>PO(0.15 mg/kg/day)<sup>¶</sup></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>24.5 ±13.7</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.5 [0.4 to 4]<sup>#</sup></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>142<sup>Þ</sup> ± 116</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>‡</paragraph></td></tr></tbody></table>
/sup> ± 116</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>‡</paragraph></td></tr></tbody></table> <table cellpadding="0.4pt" cellspacing="0pt" width="98%"><col width="18%"/><col width="14%"/><col width="15%"/><col width="17%"/><col width="17%"/><col width="18%"/><tbody><tr><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Population (No.
/sup> ± 116</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>‡</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>‡</paragraph></td></tr></tbody></table> <table cellpadding="0.4pt" cellspacing="0pt" width="98%"><col width="18%"/><col width="14%"/><col width="15%"/><col width="17%"/><col width="17%"/><col width="18%"/><tbody><tr><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Population (No. of Patients) </content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Dose</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">AUC<sub>0-t </sub></content> <content styleCode="bold">(ng·hr/mL)</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">t<sub>1/2</sub>(hr)</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">V(L/kg)</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">CI(L/hr/kg)</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph>Renal Impairment (n=12) </paragraph></td><td align="center" valign="top"><paragraph>0.02 mg/kg/4 hr IV</paragraph></td><td align="center" valign="top"><paragraph>393±123 (t=60 hr)</paragraph></td><td align="center" valign="top"><paragraph>26.3 ±9.2</paragraph></td><td align="center" valign="top"><paragraph>1.07±0.20</paragraph></td><td align="center" valign="top"><paragraph>0.038±0.014</paragraph></td></tr><tr><td align="center" rowspan="2" valign="top"><paragraph>Mild Hepatic Impairment (n=6) </paragraph></td><td align="center" valign="top"><paragraph>0.02 mg/kg/4 hr IV</paragraph></td><td align="center" valign="top"><paragraph>367±107 (t=72 hr)</paragraph></td><td align="center" valign="top"><paragraph>60.6±43.8 Range: 27.8 to 141</paragraph></td><td align="center" valign="top"><paragraph>3.1±1.6</paragraph></td><td align="center" valign="top"><paragraph>0.042±0.02</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>7.7 mg PO</paragraph></td><td align="center" valign="top"><paragraph>488±320 (t=72 hr)</paragraph></td><td align="center" valign="top"><paragraph>66.1±44.8 Range: 29.5 to 138</paragraph></td><td align="center" valign="top"><paragraph>3.7±4.7<sup>*</sup></paragraph></td><td align="center" valign="top"><paragraph>0.034±0.019<sup>*</sup></paragraph></td></tr><tr><td align="center" valign="top"><paragraph>Severe Hepatic Impairment (n=6, IV)</paragraph></td><td align="center" valign="top"><paragraph>0.02 mg/kg/4 hr IV (n=2) 0.01 mg/kg/8 hr IV (n=4)</paragraph></td><td align="center" valign="top"><paragraph>762±204 (t=120 hr) 289±117 (t=144 hr)</paragraph></td><td align="center" valign="top"><paragraph>198±158 Range: 81 to 436</paragraph></td><td align="center" valign="top"><paragraph>3.9±1.0</paragraph></td><td align="center" valign="top"><paragraph>0.017±0.013</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>(n=5, PO)<sup> †</sup></paragraph></td><td align="center" rowspan="2" valign="top"><paragraph>8 mg PO (n=1)5 mg PO (n=4) 4 mg PO (n=1)</paragraph></td><td align="center" rowspan="2" valign="top"><paragraph>658 (t=120 hr)533±156 (t=144 hr)</paragraph></td><td align="center" valign="top"><paragraph>119±35 Range: 85 to 178</paragraph></td><td align="center" valign="top"><paragraph>3.1±3.4*</paragraph></td><td align="center" valign="top"><paragraph>0.016±0.011<sup>*</sup></paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Botrule " valign="top">
></td><td align="center" valign="top"><paragraph>0.016±0.011<sup>*</sup></paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Botrule " valign="top"> <paragraph> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> </paragraph></td></tr></tbody></table>
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions ( 5.1 )]. A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% to 3%), equivalent to tacrolimus doses of 1.1 to 118 mg/kg/day or 3.3 to 354 mg/m 2 /day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown. The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis. Mutagenesis No evidence of genotoxicity was seen in bacterial ( Salmonella and E. coli ) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Impairment of Fertility Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m 2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1 mg/kg (0.8 to 2.2 times the clinical dose range), to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post- implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions ( 5.1 )]. A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% to 3%), equivalent to tacrolimus doses of 1.1 to 118 mg/kg/day or 3.3 to 354 mg/m 2 /day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown. The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis. Mutagenesis No evidence of genotoxicity was seen in bacterial ( Salmonella and E. coli ) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Impairment of Fertility Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m 2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1 mg/kg (0.8 to 2.2 times the clinical dose range), to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post- implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
14 CLINICAL STUDIES 14.1 Kidney Transplantation Tacrolimus/Azathioprine (AZA) Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded. There were 205 patients randomized to tacrolimus-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids, and azathioprine. Overall 1 year patient and graft survival were 96.1% and 89.6%, respectively. Data from this trial of tacrolimus in conjunction with azathioprine indicate that during the first 3 months of that trial, 80% of the patients maintained trough concentrations between 7 to 20 ng/mL, and then between 5 to 15 ng/mL, through 1 year. Tacrolimus/Mycophenolate Mofetil (MMF) Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multicenter trial (Study 1), 1,589 kidney transplant patients received tacrolimus (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine (CsA) regimens (Group A, n=390 and Group B, n=399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving tacrolimus/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the tacrolimus group exhibited higher estimated creatinine clearance rates (eCLcr) using the Cockcroft-Gault formula (Table 20) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or loss to follow-up (Table 21) in comparison to each of the other three groups. Patients randomized to tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions ( 6.1 )]. Table 20.
21) in comparison to each of the other three groups. Patients randomized to tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions ( 6.1 )]. Table 20. Estimated Creatinine Clearance at 12 Months (Study 1) Group eCLcr [mL/min] at Month 12 * N MEAN SD MEDIAN Treatment Difference with Group C (99.2% CI † ) (A) CsA/MMF/CS 390 56.5 25.8 56.9 -8.6 (-13.7, -3.7) (B) CsA/MMF/CS/Daclizumab 399 58.9 25.6 60.9 -6.2 (-11.2, -1.2) (C) Tac/MMF/CS/Daclizumab 401 65.1 27.4 66.2 - (D) Siro/MMF/CS/Daclizumab 399 56.2 27.4 57.3 -8.9 (-14.1, -3.9) Total 1589 59.2 26.8 60.5 Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus * All death/graft loss (n=41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n=10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n=11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. † Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. Table 21. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1) Group A Group B Group C Group D N=390 N=399 N=401 N=399 Overall Failure 141 (36.2%) 126 (31.6%) 82 (20.4%) 185 (46.4%) Components of efficacy failure BPAR 113 (29.0%) 106 (26.6%) 60 (15.0%) 152 (38.1%) Graft loss excluding death 28 (7.2%) 20 (5.0%) 12 (3.0%) 30 (7.5%) Mortality 13 (3.3%) 7 (1.8%) 11 (2.7%) 12 (3.0%) Lost to follow-up 5 (1.3%) 7 (1.8%) 5 (1.3%) 6 (1.5%) Treatment Difference of efficacy failure compared to Group C (99.2% CI*) 15.8% (7.1%, 24.3%) 11.2%(2.7%, 19.5%) - 26% (17.2%, 34.7%) Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab * Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. The protocol-specified target tacrolimus trough concentrations (C trough,Tac ) were 3 to 7 ng/mL; however, the observed median C troughs,Tac approximated 7 ng/mL throughout the 12 month trial (Table 22). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4 to 11 ng/mL through 1 year post-transplant. Table 22. Tacrolimus Whole Blood Trough Concentration Range (Study 1) Time Median (P10 to P90 * ) tacrolimus whole blood trough concentration range (ng/mL) Day 30 (N=366) 6.9 (4.4 to 11.3) Day 90 (N=351) 6.8 (4.1 to 10.7) Day 180 (N=355) 6.5 (4 to 9.6) Day 365 (N=346) 6.5 (3.8 to 10) * 10 to 90 th Percentile: range of C trough, Tac that excludes lowest 10% and highest 10% of C trough,Tac The protocol-specified target cyclosporine trough concentrations (C trough,CsA ) for Group B were 50 to 100 ng/mL; however, the observed median C troughs,CsA approximated 100 ng/mL throughout the 12 month trial. The protocol-specified target C troughs,CsA for Group A were 150 to 300 ng/mL for the first 3 months and 100 to 200 ng/mL from month 4 to month 12; the observed median C troughs, CsA approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12. While patients in all groups started MMF at 1 gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 23); approximately 50% of these MMF dose reductions were due to adverse reactions.
irst 3 months and 140 ng/mL from month 4 to month 12. While patients in all groups started MMF at 1 gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 23); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions. Table 23. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1) Time period (Days) Time-averaged MMF dose (grams per day) * Less than 2.0 2.0 Greater than 2.0 0 to 30 (N=364) 37% 60% 2% 0 to 90 (N=373) 47% 51% 2% 0 to 180 (N=377) 56% 42% 2% 0 to 365 (N=380) 63% 36% 1% Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) * Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. In a second randomized, open-label, multicenter trial (Study 2), 424 kidney transplant patients received tacrolimus (N=212) or cyclosporine (N=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the tacrolimus/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving tacrolimus/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to over-immunosuppression (Table 24). Table 24. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2) Tacrolimus/MMF Cyclosporine/MMF (N=212) (N=212) Overall Failure 32 (15.1%) 36 (17.0%) Components of efficacy failure BPAR 16 (7.5%) 29 (13.7%) Graft loss excluding death 6 (2.8%) 4 (1.9%) Mortality 9 (4.2%) 5 (2.4%) Lost to follow-up 4 (1.9%) 1 (0.5%) Treatment Difference of efficacy failure compared to tacrolimus/MMF group (95% CI*) 1.9% (-5.2%, 9.0%) * 95% confidence interval calculated using Fisher's Exact Test. The protocol-specified target tacrolimus whole blood trough concentrations (C trough,Tac ) in Study 2 were 7 to 16 ng/mL for the first three months and 5 to 15 ng/mL thereafter. The observed median C troughs,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 25). Approximately 80% of patients maintained tacrolimus whole blood trough concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year. Table 25. Tacrolimus Whole Blood Trough Concentration Range (Study 2) Time Median (P10 to P90 * ) tacrolimus whole blood trough concentration range (ng/mL) Day 30 (N=174) 10.5 (6.3 to 16.8) Day 60 (N=179) 9.2 (5.9 to 15.3) Day 120 (N=176) 8.3 (4.6 to 13.3) Day 180 (N=171) 7.8 (5.5 to 13.2) Day 365 (N=178) 7.1 (4.2 to 12.4) *10 to 90 th Percentile: range of C trough,Tac that excludes lowest 10% and highest 10% of C trough, Tac. The protocol-specified target cyclosporine whole blood concentrations (C trough,CsA ) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median C troughs, CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12. Patients in both groups started MMF at 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the tacrolimus/MMF group (Table 26) and in 47% of patients in the cyclosporine/MMF group.
ted 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12. Patients in both groups started MMF at 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the tacrolimus/MMF group (Table 26) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the tacrolimus/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions ( 6.1 )]. Table 26. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2) Time period (Days) Time-averaged MMF dose (g/day)* Less than 2.0 2.0 Greater than 2.0 0 to 30 (N=212) 25% 69% 6% 0 to 90 (N=212) 41% 53% 6% 0 to 180 (N=212) 52% 41% 7% 0 to 365 (N=212) 62% 34% 4% Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) * Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods. 14.2 Liver Transplantation The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation. In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed. In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases. One-year patient survival and graft survival in the tacrolimus-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and tacrolimus-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and tacrolimus-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral tacrolimus dosing was 2 days. Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients are often maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.
tained between 5 to 20 ng/mL. Long-term post-transplant patients are often maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL. Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 14.3 Heart Transplantation Two open-label, randomized, comparative trials evaluated the safety and efficacy of tacrolimus-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with tacrolimus or cyclosporine modified for 18 months. In a 3-arm trial conducted in the U.S., 331 patients received corticosteroids and tacrolimus plus sirolimus, tacrolimus plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year. In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the tacrolimus plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from 1 week to 3 months post-transplant, approximately 80% of patients maintained trough concentrations between 8 to 20 ng/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to 18 ng/mL. The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose tacrolimus; however, this regimen was associated with increased risk of wound-healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions (5.10 )].
<table width="100%"><col width="34%"/><col width="12%"/><col width="13%"/><col width="12%"/><col width="14%"/><col width="14%"/><tbody><tr><td rowspan="2" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Group </content></paragraph></td><td align="center" colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">eCLcr [mL/min] at Month 12<sup>*</sup></content></paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">MEAN</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">SD</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">MEDIAN</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Treatment Difference with Group C</content> <content styleCode="bold">(99.2% CI</content><sup>†</sup><content styleCode="bold">)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>(A) CsA/MMF/CS </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>390 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>56.5 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>25.8 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>56.9 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-8.6 (-13.7, -3.7) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>(B) CsA/MMF/CS/Daclizumab </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>399 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>58.9 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>25.6 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>60.9 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-6.2 (-11.2, -1.2) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>(C) Tac/MMF/CS/Daclizumab </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>401 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>65.1 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>27.4 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>66.2 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>(D) Siro/MMF/CS/Daclizumab </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>399 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>56.2 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>27.4 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>57.3 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign
ter" styleCode="Lrule Botrule " valign="top"><paragraph>56.2 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>27.4 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>57.3 </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign ="top"><paragraph>-8.9 (-14.1, -3.9) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Total </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>1589 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>59.2 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>26.8 </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>60.5 </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" colspan="6" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus </paragraph></td></tr></tbody></table>
ule " valign="top"><paragraph>60.5 </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" colspan="6" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus </paragraph></td></tr></tbody></table> <table width="100%"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Group A </content></paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Group B </content></paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Group C </content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Group D </content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"/><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N=390 </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N=399 </content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N=401 </content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N=399 </content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Overall Failure </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>141 (36.2%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>126 (31.6%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>82 (20.4%) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>185 (46.4%) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Components of efficacy failure </paragraph></td><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>BPAR </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>113 (29.0%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>106 (26.6%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>60 (15.0%) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>152 (38.1%) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Graft loss excluding death </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>28 (7.2%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>20 (5.0%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>12 (3.0%) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30 (7.5%) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Mortality </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>13 (3.3%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>7 (1.8%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>11 (2.7%) </paragraph></td><td align="center" sty
ph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>13 (3.3%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>7 (1.8%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>11 (2.7%) </paragraph></td><td align="center" sty leCode="Rrule Lrule Botrule " valign="top"><paragraph>12 (3.0%) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Lost to follow-up </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>5 (1.3%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>7 (1.8%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>5 (1.3%) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (1.5%) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Treatment Difference of efficacy failure compared to Group C (99.2% CI*)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>15.8% (7.1%, 24.3%)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>11.2%(2.7%, 19.5%) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> -</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26% (17.2%, 34.7%)</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab </paragraph></td></tr></tbody></table>
eCode="Rrule Lrule Botrule " valign="top"><paragraph>26% (17.2%, 34.7%)</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab </paragraph></td></tr></tbody></table> <table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Time </content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Median (P10 to P90</content><sup>*</sup><content styleCode="bold">) tacrolimus whole blood trough concentration range </content> <content styleCode="bold">(ng/mL)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Day 30 (N=366) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6.9 (4.4 to 11.3) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Day 90 (N=351) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6.8 (4.1 to 10.7) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Day 180 (N=355) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6.5 (4 to 9.6) </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Day 365 (N=346) </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6.5 (3.8 to 10) </paragraph></td></tr></tbody></table>
er" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6.5 (4 to 9.6) </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Day 365 (N=346) </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6.5 (3.8 to 10) </paragraph></td></tr></tbody></table> <table width="100%"><col width="33%"/><col width="22%"/><col width="22%"/><col width="23%"/><tbody><tr><td rowspan="2" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Time period (Days) </content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Time-averaged MMF dose (grams per day)<sup>*</sup> </content></paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>Less than 2.0</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>2.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Greater than 2.0</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>0 to 30 (N=364) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>60%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>0 to 90 (N=373) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>47%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>51%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>0 to 180 (N=377) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>42%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>0 to 365 (N=380) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>63%</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>36%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td align="center" colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) </paragraph></td></tr></tbody></table>
6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td align="center" colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) </paragraph></td></tr></tbody></table> <table width="100%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tacrolimus/MMF </content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cyclosporine/MMF </content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"/><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">(N=212) </content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">(N=212) </content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Overall Failure </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>32 (15.1%) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36 (17.0%) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Components of efficacy failure </paragraph></td><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>BPAR </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>16 (7.5%) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29 (13.7%) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Graft loss excluding death </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>6 (2.8%) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (1.9%) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Mortality </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>9 (4.2%) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (2.4%) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Lost to follow-up </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>4 (1.9%) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5%) </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Treatment Difference of efficacy failure compared to tacrolimus/MMF group (95% CI*) </paragraph></td><td styleCode="Botrule Lrule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1.9% (-5.2%, 9.0%) </paragraph></td></tr></tbody></table>
"Botrule Lrule " valign="top"><paragraph>Treatment Difference of efficacy failure compared to tacrolimus/MMF group (95% CI*) </paragraph></td><td styleCode="Botrule Lrule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1.9% (-5.2%, 9.0%) </paragraph></td></tr></tbody></table> <table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Time </content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Median (P10 to P90<sup>*</sup>) tacrolimus whole blood trough concentration range</content> <content styleCode="bold">(ng/mL) </content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Day 30 (N=174) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10.5 (6.3 to 16.8) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Day 60 (N=179) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9.2 (5.9 to 15.3) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Day 120 (N=176) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8.3 (4.6 to 13.3) </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Day 180 (N=171) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.8 (5.5 to 13.2) </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Day 365 (N=178) </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7.1 (4.2 to 12.4) </paragraph></td></tr></tbody></table>
tyleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.8 (5.5 to 13.2) </paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Day 365 (N=178) </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7.1 (4.2 to 12.4) </paragraph></td></tr></tbody></table> <table width="100%"><col width="33%"/><col width="22%"/><col width="22%"/><col width="23%"/><thead><tr><th align="left" rowspan="2" styleCode="Botrule Lrule Toprule " valign="top"><content styleCode="bold">Time period (Days) </content></th><th align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Time-averaged MMF dose (g/day)*</content></th></tr><tr><th align="left" styleCode="Lrule Botrule " valign="top"><content styleCode="bold">Less than 2.0</content></th><th align="left" styleCode="Lrule Botrule " valign="top"><content styleCode="bold">2.0 </content></th><th align="left" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Greater than 2.0 </content></th></tr></thead><tbody><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>0 to 30 (N=212) </paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>25% </paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>69% </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>0 to 90 (N=212) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>41% </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>53% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>0 to 180 (N=212) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>52% </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>41% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7% </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>0 to 365 (N=212) </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>62% </paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>34% </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4% </paragraph></td></tr><tr><td align="center" colspan="4" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) </paragraph></td></tr></tbody></table>
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Tacrolimus Capsules, USP Tacrolimus Capsules USP, 0.5 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, dark yellow opaque cap imprinted with ‘0.5 MG’ and dark yellow opaque body imprinted with ‘RDY 525’using red ink and are supplied in Cartons of 100 capsules (10 capsules each blister pack x 10), NDC 0904-6623-61 Tacrolimus Capsules USP, 5 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, dark grayish red opaque cap imprinted with ‘5 MG’ and dark grayish red opaque body imprinted with ‘RDY 527’ using white ink and are supplied in Cartons of 100 capsules (10 capsules each blister pack x 10), NDC 0904-6624-61 WARNING: These Unit Dose packages are not child resistant and are Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Note: Tacrolimus capsules, USP are not filled to maximum capsule capacity. Capsule contains labeled amount. Store and Dispense Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. 16.4 Handling and Disposal Tacrolimus can cause fetal harm. Tacrolimus capsules should not be opened or crushed. Wearing disposable gloves is recommended during dilution of the injection in the hospital and when wiping any spills. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in tacrolimus capsules. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures 1 .
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). 17.1 Administration Advise the patient or caregiver to: • Inspect their tacrolimus medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for tacrolimus capsules. • Take tacrolimus at the same 12 hour intervals every day to achieve consistent blood concentrations. • Take tacrolimus consistently either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus. • Not to eat grapefruit or drink grapefruit juice in combination with tacrolimus [see Drug Interactions (7.2) ]. 17.2 Development of Lymphoma and Other Malignancies Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Warnings and Precautions ( 5.1 )]. 17.3 Increased Risk of Infection Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Warnings and Precautions (5.2 )]. 17.4 New Onset Diabetes After Transplant Inform patients that tacrolimus can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger [see Warnings and Precautions ( 5.4 )]. 17.5 Nephrotoxicity Inform patients that tacrolimus can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions ( 5.5 )]. 17.6 Neurotoxicity Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions ( 5.6 )]. 17.7 Hyperkalemia Inform patients that tacrolimus can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions ( 5.7 )]. 17.8 Hypertension Inform patients that tacrolimus can cause high blood pressure which may require treatment with antihypertensive therapy. Advise patients to monitor their blood pressure [see Warnings and Precautions ( 5.8 )]. 17.9 Thrombotic Microangiopathy Inform patients that tacrolimus capsules can cause blood clotting problems. The risk of this occurring increases when patients take tacrolimus capsules and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria. [see Warnings and Precautions ( 5.16 )].
occurring increases when patients take tacrolimus capsules and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria. [see Warnings and Precautions ( 5.16 )]. 17.10 Drug Interactions Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription medicines and nonprescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice [see Drug Interactions ( 7 )]. 17.11 Pregnancy, Lactation and Infertility Inform women of childbearing potential that tacrolimus can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations ( 8.1 , 8.2 , 8.3 )]. Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ [see Use in Specific Populations ( 8.1 )]. Based on animal studies, tacrolimus may affect fertility in males and females [see Nonclinical Toxicology ( 13.1 )]. 17.12 Myocardial Hypertrophy Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure). 17.13 Immunizations Inform patients that tacrolimus can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions ( 5.14 )]. All other trademarks and registered trademarks are the property of their respective owners . Rx Only Manufactured by Dr. Reddy’s Laboratories Limited Bachupally – 500 090 INDIA Packaged and Distributed by: MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA Refer to package label for Distributor's NDC Number Revised: 11/2023
Patient Information Tacrolimus (ta kroe′ li mus) Capsules, for oral use Read this Patient Information before you start taking tacrolimus capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about tacrolimus capsules? Tacrolimus capsules can cause serious side effects, including: • Increased risk of cancer. People who take tacrolimus capsules have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma). • Increased risk of infection. Tacrolimus is a medicine that affects your immune system. Tacrolimus capsules can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving tacrolimus capsules that can cause death. Call your healthcare provider right away if you have any symptoms of an infection, including: • fever • muscle aches • sweats or chills • cough or flu-like symptoms • warm, red, or painful areas on your skin What are tacrolimus capsules? • Tacrolimus capsules are a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver or heart transplant. • Tacrolimus capsules is a type of tacrolimus immediate-release drug and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you. Who should not take tacrolimus capsules? Do not take tacrolimus capsules if you: • are allergic to tacrolimus or any of the ingredients in tacrolimus capsules. See the end of this leaflet for a complete list of ingredients in tacrolimus capsules. What should I tell my healthcare provider before taking tacrolimus capsules? Before taking tacrolimus capsules, tell your healthcare provider about all of your medical conditions, including if you: • plan to receive any vaccines. People taking tacrolimus capsules should not receive live vaccines. • have or have had liver, kidney or heart problems. • are pregnant or plan to become pregnant. Tacrolimus capsules can harm your unborn baby. o If you are able to become pregnant, you should use effective birth control before and during treatment with tacrolimus. Talk to your healthcare provider before starting treatment with tacrolimus about birth control methods that may be right for you. o Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus. Talk to your healthcare provider before starting treatment with tacrolimus about birth control methods that may be right for you. o There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with tacrolimus. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/. • are breastfeeding or plan to breastfeed. Tacrolimus passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking tacrolimus capsules. • plan to have children. Tacrolimus capsules may affect the ability to have children in females and males (fertility problems).
rg/. • are breastfeeding or plan to breastfeed. Tacrolimus passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking tacrolimus capsules. • plan to have children. Tacrolimus capsules may affect the ability to have children in females and males (fertility problems). Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine, including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements. Especially tell your healthcare provider if you take: • sirolimus (RAPAMUNE): You should not take tacrolimus capsules if you take sirolimus. • cyclosporine (GENGRAF, NEORAL, and SANDIMMUNE) • medicines called aminoglycosides that are used to treat bacterial infections • ganciclovir (CYTOVENE IV, VALCYTE) • amphotericin B (ABELCET, AMBISOME) • cisplatin • antiviral medicines called nucleoside reverse transcriptase inhibitors • antiviral medicines called protease inhibitors • water pill (diuretic) • medicine to treat high blood pressure • nelfinavir (VIRACEPT) • telaprevir (INCIVEK) • boceprevir • ritonavir (KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR) • letermovir (PREVYMIS) • ketoconazole • itraconazole (ONMEL, SPORANOX) • voriconazole (VFEND) • caspofungin (CANCIDAS) • clarithromycin (BIAXIN, BIAXIN XL, PREVPAC) • rifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE) • rifabutin (MYCOBUTIN) • amiodarone (NEXTERONE, PACERONE) • cannabidiol (EPIDIOLEX) Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. Tacrolimus capsules may affect the way other medicines work, and other medicines may affect how tacrolimus capsules work. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take tacrolimus capsules? • Take tacrolimus capsules exactly as your healthcare provider tells you to take it. • Your healthcare provider will tell you how much tacrolimus to take and when to take it.Your healthcare provider may change your tacrolimus capsules dose if needed. Do not stop taking or change your dose of tacrolimus capsules without talking to your healthcare provider. • Take tacrolimus capsules with or without food. • Take tacrolimus capsules the same way every day. For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food. • Take tacrolimus capsules at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m. you should take your second dose at 7:00 p.m. • Taking tacrolimus capsules at the same time each day helps to keep the amount of medicine in your body at a steady level. • If you take too much tacrolimus capsules, call your healthcare provider or go to the nearest hospital emergency room right away. Tacrolimus capsules: • Do not open or crush tacrolimus capsules. What should I avoid while taking tacrolimus capsules? • While you take tacrolimus capsules you should not receive any live vaccines • Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF). Do not eat grapefruit or drink grapefruit juice during treatment with tacrolimus . What are the possible side effects of tacrolimus capsules? Tacrolimus capsules may cause serious side effects, including: • See “What is the most important information I should know about tacrolimus capsules?” • problems from medicine errors. People who take tacrolimus have sometimes been given the wrong type of tacrolimus product.
possible side effects of tacrolimus capsules? Tacrolimus capsules may cause serious side effects, including: • See “What is the most important information I should know about tacrolimus capsules?” • problems from medicine errors. People who take tacrolimus have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as tacrolimus capsules or granules and cannot be substituted for each other. Check your tacrolimus when you get a new prescription and before you take it to make sure you have received tacrolimus capsules. • Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine. • high blood sugar (diabetes). Your healthcare provider may do blood tests to check for diabetes while you take tacrolimus capsules. Call your healthcare provider right away if you have any symptoms of high blood sugar, including: o frequent urination o increased thirst or hunger o blurred vision o confusion o drowsiness o loss of appetite o fruity smell on your breath o nausea, vomiting, or stomach pain • kidney problems. Kidney problems are a serious and common side effect of tacrolimus. Your healthcare provider may do blood tests to check your kidney function while you take tacrolimus capsules. • nervous system problems. Nervous system problems are a serious and common side effect of tacrolimus . Call your healthcare provider right away if you get any of these symptoms while taking tacrolimus capsules. These could be signs of a serious nervous system problem: o headache o confusion o seizures o changes in your vision o changes in behavior o coma o tremors o numbness and tingling • high levels of potassium in your blood. Your healthcare provider may do blood tests to check your potassium level while you take tacrolimus capsules • high blood pressure. High blood pressure is a serious and common side effect of tacrolimus. Your healthcare provider will monitor your blood pressure while you take tacrolimus and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home. • changes in the electrical activity of your heart (QT prolongation) . • heart problems (myocardial hypertrophy). Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking tacrolimus capsules: o shortness of breath o chest pain o feel lightheaded o feel faint • severe low red blood cell count (anemia). • blood clotting problems: Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase. The most common side effects of tacrolimus capsules in people who have received a kidney, liver or heart transplant are: • infections in general, including cytomegalovirus (cmv) infection • tremors (shaking of the body) • constipation • diarrhea • headache • stomach pain • trouble sleeping • nausea • high blood sugar (diabetes) • low levels of magnesium in your blood • low levels of phosphate in your blood • swelling of the hands, legs, ankles, or feet • weakness • pain • high levels of fat in your blood • high levels of potassium in your blood • low red blood cell count (anemia) • low white blood cell count • fever • numbness or tingling in your hands and feet • inflammation of your airway (bronchitis) • fluid around your heart Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of tacrolimus capsules.
• low white blood cell count • fever • numbness or tingling in your hands and feet • inflammation of your airway (bronchitis) • fluid around your heart Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of tacrolimus capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store tacrolimus capsules? • Store Tacrolimus capsules at room temperature between 20°C to 25°C (68°F to 77°F) Keep tacrolimus capsules and all medicines out of the reach of children. General information about the safe and effective use of tacrolimus capsules • Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tacrolimus capsules for a condition for which it was not prescribed. Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about tacrolimus that is written for health professionals. • This Patient Information leaflet summarizes the most important information about tacrolimus capsules. If you would like more information, talk to your healthcare provider. What are the ingredients in tacrolimus capsules? Active ingredient: tacrolimus Inactive ingredients: croscarmellose sodium, lactose monohydrate and magnesium stearate. The 0.5 mg capsule shell contains gelatin, iron oxide red, iron oxide yellow and titanium dioxide, the 1 mg capsule shell contains gelatin and titanium dioxide and the 5 mg capsule shell contains gelatin, iron oxide red, iron oxide black, and titanium dioxide. All other trademarks and registered trademarks are the property of their respective owners . For more information call 1-888-375-3784. Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. This Patient Information has been approved by the U.S. Food and Drug Administration. Rx Only Manufactured by Dr. Reddy’s Laboratories Limited Bachupally – 500 090 INDIA Packaged and Distributed by: MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA Refer to package label for Distributor's NDC Number Revised: 11/20223 Dispense with Patient Information Sheet available at: www.drreddys.com/pi/tacrolimuscaps.pdf
<table width="100%"><col width="100%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Patient Information</content> <content styleCode="bold">Tacrolimus </content>(ta kroe′ li mus)<content styleCode="bold"> Capsules, for oral use</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Read this Patient Information before you start taking tacrolimus capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about tacrolimus capsules?</content> <content styleCode="bold">Tacrolimus capsules can cause serious side effects, including:</content> <content styleCode="bold">• Increased risk of cancer. </content>People who take tacrolimus capsules have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma). • <content styleCode="bold">Increased risk of infection. </content>Tacrolimus is a medicine that affects your immune system. Tacrolimus capsules can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving tacrolimus capsules that can cause death. <content styleCode="bold">Call your healthcare provider right away if you have any symptoms of an infection, including: </content></paragraph><list listType="unordered"><item><caption>•</caption>fever </item><item><caption>•</caption>muscle aches</item><item><caption>•</caption>sweats or chills</item><item><caption>•</caption>cough or flu-like symptoms</item><item><caption>•</caption>warm, red, or painful areas on your skin</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are tacrolimus capsules?</content></paragraph><list listType="unordered"><item><caption>•</caption>Tacrolimus capsules are a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver or heart transplant. </item><item><caption>•</caption>Tacrolimus capsules is a type of tacrolimus immediate-release drug and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you. </item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Who should not take tacrolimus capsules?</content> <content styleCode="bold">Do not take tacrolimus capsules if you:</content></paragraph><list listType="unordered"><item><caption>•</caption> are allergic to tacrolimus or any of the ingredients in tacrolimus capsules.
n="top"><paragraph><content styleCode="bold">Who should not take tacrolimus capsules?</content> <content styleCode="bold">Do not take tacrolimus capsules if you:</content></paragraph><list listType="unordered"><item><caption>•</caption> are allergic to tacrolimus or any of the ingredients in tacrolimus capsules. See the end of this leaflet for a complete list of ingredients in tacrolimus capsules.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I tell my healthcare provider before taking tacrolimus capsules?</content> <content styleCode="bold">Before taking tacrolimus capsules, tell your healthcare provider about all of your medical conditions, including if you: </content></paragraph><list listType="unordered"><item><caption>•</caption>plan to receive any vaccines. People taking tacrolimus capsules should not receive live vaccines. </item><item><caption>•</caption>have or have had liver, kidney or heart problems.</item><item><caption>•</caption>are pregnant or plan to become pregnant. Tacrolimus capsules can harm your unborn baby. <list listType="unordered"><item><caption>o</caption>If you are able to become pregnant, you should use effective birth control before and during treatment with tacrolimus. Talk to your healthcare provider before starting treatment with tacrolimus about birth control methods that may be right for you. </item><item><caption>o</caption>Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus. Talk to your healthcare provider before starting treatment with tacrolimus about birth control methods that may be right for you. </item><item><caption>o</caption>There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with tacrolimus. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/. </item></list></item><item><caption>•</caption>are breastfeeding or plan to breastfeed. Tacrolimus passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking tacrolimus capsules. </item><item><caption>•</caption>plan to have children. Tacrolimus capsules may affect the ability to have children in females and males (fertility problems).</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine, </content>including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements. <content styleCode="bold">Especially tell your healthcare provider if you take:</content> • sirolimus (RAPAMUNE): You should not take tacrolimus capsules if you take sirolimus.
aking a medicine, </content>including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements. <content styleCode="bold">Especially tell your healthcare provider if you take:</content> • sirolimus (RAPAMUNE): You should not take tacrolimus capsules if you take sirolimus. • cyclosporine (GENGRAF, NEORAL, and SANDIMMUNE) • medicines called aminoglycosides that are used to treat bacterial infections • ganciclovir (CYTOVENE IV, VALCYTE) • amphotericin B (ABELCET, AMBISOME) • cisplatin • antiviral medicines called nucleoside reverse transcriptase inhibitors • antiviral medicines called protease inhibitors • water pill (diuretic) • medicine to treat high blood pressure • nelfinavir (VIRACEPT) • telaprevir (INCIVEK) • boceprevir • ritonavir (KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR) • letermovir (PREVYMIS) • ketoconazole • itraconazole (ONMEL, SPORANOX) • voriconazole (VFEND) • caspofungin (CANCIDAS) • clarithromycin (BIAXIN, BIAXIN XL, PREVPAC) • rifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE) • rifabutin (MYCOBUTIN) • amiodarone (NEXTERONE, PACERONE) • cannabidiol (EPIDIOLEX) Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. Tacrolimus capsules may affect the way other medicines work, and other medicines may affect how tacrolimus capsules work. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take tacrolimus capsules?</content> </paragraph><list listType="unordered"><item><caption>•</caption>Take tacrolimus capsules exactly as your healthcare provider tells you to take it.</item><item><caption>•</caption>Your healthcare provider will tell you how much tacrolimus to take and when to take it.Your healthcare provider may change your tacrolimus capsules dose if needed. <content styleCode="bold">Do not </content>stop taking or change your dose of tacrolimus capsules without talking to your healthcare provider.</item><item><caption>•</caption>Take tacrolimus capsules with or without food.</item><item><caption>•</caption>Take tacrolimus capsules the same way every day. For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food.</item><item><caption>•</caption>Take tacrolimus capsules at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m.
olimus capsules the same way every day. For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food.</item><item><caption>•</caption>Take tacrolimus capsules at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m. you should take your second dose at 7:00 p.m.</item><item><caption>•</caption>Taking tacrolimus capsules at the same time each day helps to keep the amount of medicine in your body at a steady level.</item><item><caption>•</caption>If you take too much tacrolimus capsules, call your healthcare provider or go to the nearest hospital emergency room right away.</item></list><paragraph><content styleCode="bold">Tacrolimus capsules:</content></paragraph><list listType="unordered"><item><caption>•</caption><content styleCode="bold">Do not</content> open or crush tacrolimus capsules.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I avoid while taking tacrolimus capsules?</content></paragraph><list listType="unordered"><item><caption>•</caption>While you take tacrolimus capsules you should not receive any live vaccines</item><item><caption>•</caption>Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).</item></list><paragraph><content styleCode="bold">Do not </content>eat grapefruit or drink grapefruit juice during treatment with tacrolimus .</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of tacrolimus capsules?</content> <content styleCode="bold">Tacrolimus capsules may cause serious side effects, including:</content> </paragraph><list listType="unordered"><item><caption>•</caption>See<content styleCode="bold"> “What is the most important information I should know about tacrolimus capsules?”</content></item><item><caption>•</caption><content styleCode="bold">problems from medicine errors. </content>People who take tacrolimus have sometimes been given the wrong type of tacrolimus product. <content styleCode="bold">Tacrolimus extended-release medicines are not the same as tacrolimus capsules or granules </content>and cannot be substituted for each other. <content styleCode="bold">Check your tacrolimus when you get a new prescription and before you take it to make sure you have received tacrolimus capsules.</content></item><item><caption>•</caption>Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine. </item><item><caption>•</caption><content styleCode="bold">high blood sugar (diabetes). </content>Your healthcare provider may do blood tests to check for diabetes while you take tacrolimus capsules. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:<list listType="unordered"><item><caption>o</caption>frequent urination</item><item><caption>o</caption>increased thirst or hunger</item><item><caption>o</caption>blurred vision</item><item><caption>o</caption>confusion </item><item><caption>o</caption>drowsiness</item><item><caption>o</caption>loss of appetite</item><item><caption>o</caption>fruity smell on your breath</item><item><caption>o</caption>nausea, vomiting, or stomach pain </item></list></item><item><caption>•</caption><content styleCode="bold">kidney problems. </content>Kidney problems are a serious and common side effect of tacrolimus.
on>loss of appetite</item><item><caption>o</caption>fruity smell on your breath</item><item><caption>o</caption>nausea, vomiting, or stomach pain </item></list></item><item><caption>•</caption><content styleCode="bold">kidney problems. </content>Kidney problems are a serious and common side effect of tacrolimus. Your healthcare provider may do blood tests to check your kidney function while you take tacrolimus capsules.</item><item><caption>•</caption><content styleCode="bold">nervous system problems. </content>Nervous system problems are a serious and common side effect of tacrolimus<content styleCode="bold">. </content>Call your healthcare provider right away if you get any of these symptoms while taking tacrolimus capsules. These could be signs of a serious nervous system problem:<list listType="unordered"><item><caption>o</caption>headache </item><item><caption>o</caption>confusion </item><item><caption>o</caption>seizures</item><item><caption>o</caption> changes in your vision </item><item><caption>o</caption>changes in behavior</item><item><caption>o</caption>coma</item><item><caption>o</caption>tremors</item><item><caption>o</caption>numbness and tingling</item></list></item><item><caption>•</caption><content styleCode="bold">high levels of potassium in your blood. </content>Your healthcare provider may do blood tests to check your potassium level while you take tacrolimus capsules</item><item><caption>•</caption><content styleCode="bold">high blood pressure. </content>High blood pressure is a serious and common side effect of tacrolimus. Your healthcare provider will monitor your blood pressure while you take tacrolimus and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.</item><item><caption>•</caption><content styleCode="bold">changes in the electrical activity of your heart (QT prolongation)</content>.</item><item><caption>•</caption><content styleCode="bold">heart problems (myocardial hypertrophy). </content>Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking tacrolimus capsules:<list listType="unordered"><item><caption>o</caption>shortness of breath </item><item><caption>o</caption>chest pain </item><item><caption>o</caption>feel lightheaded</item><item><caption>o</caption> feel faint </item></list></item><item><caption>•</caption><content styleCode="bold">severe low red blood cell count (anemia).</content></item><item><caption>•</caption><content styleCode="bold">blood clotting problems: </content>Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase.
</content>Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase. </item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">The most common side effects of tacrolimus capsules in people who have received a kidney, liver or heart transplant are:</content></paragraph><list listType="unordered"><item><caption>•</caption>infections in general, including cytomegalovirus (cmv) infection</item><item><caption>•</caption>tremors (shaking of the body)</item><item><caption>•</caption>constipation</item><item><caption>•</caption>diarrhea</item><item><caption>•</caption>headache</item><item><caption>•</caption>stomach pain</item><item><caption>•</caption>trouble sleeping</item><item><caption>•</caption>nausea</item><item><caption>•</caption>high blood sugar (diabetes)</item><item><caption>•</caption>low levels of magnesium in your blood</item><item><caption>•</caption>low levels of phosphate in your blood</item><item><caption>•</caption>swelling of the hands, legs, ankles, or feet</item><item><caption>•</caption>weakness</item><item><caption>•</caption>pain</item><item><caption>•</caption>high levels of fat in your blood</item><item><caption>•</caption>high levels of potassium in your blood</item><item><caption>•</caption>low red blood cell count (anemia)</item><item><caption>•</caption>low white blood cell count </item><item><caption>•</caption>fever</item><item><caption>•</caption> numbness or tingling in your hands and feet </item><item><caption>•</caption>inflammation of your airway (bronchitis) </item><item><caption>•</caption>fluid around your heart Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of tacrolimus capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store tacrolimus capsules?</content> </paragraph><list listType="unordered"><item><caption>•</caption>Store Tacrolimus capsules at room temperature between 20°C to 25°C (68°F to 77°F) </item></list><paragraph><content styleCode="bold">Keep tacrolimus capsules and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of tacrolimus capsules</content></paragraph><list listType="unordered"><item><caption>•</caption>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tacrolimus capsules for a condition for which it was not prescribed. Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about tacrolimus that is written for health professionals. </item><item><caption>•</caption>This Patient Information leaflet summarizes the most important information about tacrolimus capsules. If you would like more information, talk to your healthcare provider.
pharmacist or healthcare provider for information about tacrolimus that is written for health professionals. </item><item><caption>•</caption>This Patient Information leaflet summarizes the most important information about tacrolimus capsules. If you would like more information, talk to your healthcare provider. </item></list></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in tacrolimus capsules?</content> Active ingredient: tacrolimus Inactive ingredients: croscarmellose sodium, lactose monohydrate and magnesium stearate. The 0.5 mg capsule shell contains gelatin, iron oxide red, iron oxide yellow and titanium dioxide, the 1 mg capsule shell contains gelatin and titanium dioxide and the 5 mg capsule shell contains gelatin, iron oxide red, iron oxide black, and titanium dioxide. All other trademarks and registered trademarks are the property of their respective owners . For more information call 1-888-375-3784.</paragraph></td></tr></tbody></table>
<table width="100%" styleCode="Noautorules"><col width="81.950%" align="left"/><col width="18.050%" align="left"/><tbody><tr><td align="left" valign="top">Warnings and Precautions ( <linkHtml href="#s23">5.5</linkHtml>, <linkHtml href="#s28">5.10</linkHtml>, <linkHtml href="#s34">5.16</linkHtml>) </td><td align="right" valign="top">11/2022</td></tr></tbody></table>
WARNING: MALIGNANCIES and SERIOUS INFECTIONS Increased risk for developing serious infections and malignancies with Tacrolimus Injection or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 ) WARNING: MALIGNANCIES and SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Increased risk for developing serious infections and malignancies with Tacrolimus Injection or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 )
1 INDICATIONS AND USAGE Tacrolimus is a is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult patients receiving allogeneic liver, kidney or heart transplants, and pediatric patients receiving allogeneic liver transplants in combination with other immunosuppressants. ( 1.1 ) 1.1 Prophylaxis of Organ Rejection in Kidney, Liver or Heart Transplant Tacrolimus is indicated for the prophylaxis of organ rejection, in adult patients receiving allogeneic kidney transplant [see Clinical Studies ( 14.1 )], liver transplants [see Clinical Studies ( 14.2 )] and heart transplant [see Clinical Studies ( 14.3 )], and pediatric patients receiving allogeneic liver transplants [see Clinical Studies ( 14.2 )] in combination with other immunosuppressants. Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf ® (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
2 DOSAGE AND ADMINISTRATION Intravenous (IV) use recommended for patients who cannot tolerate oral formulations (capsules or suspension). ( 2.1 , 2.2 ) Therapeutic drug monitoring is recommended. ( 2.1 , 2.6 ) Avoid eating grapefruit or drinking grapefruit juice. ( 2.1 ) See dosage adjustments for African-American patients ( 2.2 ), hepatic and renal impaired. ( 2.4 , 2.5 ) For complete dosing information, see Full Prescribing Information. 2.1 Important Administration Instructions Tacrolimus should not be used without supervision by a physician with experience in immunosuppressive therapy. 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. General Administration Instructions Patients should not eat grapefruit or drink grapefruit juice in combination with Tacrolimus [see Drug Interactions ( 7.2 )]. Tacrolimus should not be used simultaneously with cyclosporine. Tacrolimus or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed. Therapeutic drug monitoring (TDM) is recommended for all patients receiving Tacrolimus [see Dosage and Administration ( 2.6 )]. 2.2 Dosage Recommendations for Adult Kidney, Liver, or Heart Transplant Patients - Injection 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 Prograf® capsules should be given 8-12 hours after discontinuing the intravenous infusion. The recommended starting dose of Tacrolimus injection is 0.03-0.05 mg/kg/day in kidney or liver transplant, 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. 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 Dosage Recommendations for Pediatric Liver Transplant Patients Intravenous Injection If a patient is unable to receive an oral formulation, the patient may be started on tacrolimus injection.
jection. Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions ( 5.9 )] . 2.3 Dosage Recommendations for Pediatric Liver Transplant Patients Intravenous Injection If a patient is unable to receive an oral formulation, the patient may be started on tacrolimus injection. For pediatric liver transplant patients, the intravenous dose is 0.03–0.05 mg/kg/day. Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf ® (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Dosage Modification for Patients with Renal Impairment Due to its potential for nephrotoxicity, consider dosing tacrolimus injection at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required. In kidney transplant patients with post-operative oliguria, the initial dose of tacrolimus should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] . 2.5 Dosage Modification for Patients with Hepatic Impairment Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh ≥ 10) may require lower doses of tacrolimus. Close monitoring of blood concentrations is warranted. The use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. These patients should be monitored closely, and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )]. 2.6 Therapeutic Drug Monitoring Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments, and compliance. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation. The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure. Methods commonly used for the assay of tacrolimus include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore, assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed.
ays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer, they should be deep frozen at -20°C. One study showed drug recovery > 90% for samples stored at -20°C for 6 months, with reduced recovery observed after 6 months. 2.7 Preparation and Administration Instructions of Tacrolimus Injection for Pharmacists Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures 1 [see How Supplied/ Storage and Handling ( 16.4 )] . Tacrolimus injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a polyvinyl chloride (PVC) container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Due to the chemical instability of tacrolimus in alkaline media, Tacrolimus injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).
4 CONTRAINDICATIONS Tacrolimus injection is 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 )] . Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 )
5 WARNINGS AND PRECAUTIONS New Onset Diabetes After Transplant: Monitor blood glucose. ( 5.4 ) Nephrotoxicity (acute and/or chronic): Reduce the dose; use caution with other nephrotoxic drugs. ( 5.5 ) Neurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue tacrolimus. ( 5.6 ) Hyperkalemia: Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia. ( 5.7 ) Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions. ( 5.8 ) Anaphylactic Reactions with intravenous formulation: Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis. ( 5.9 ) Not recommended for use with sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions. ( 5.10 ) Myocardial Hypertrophy: Consider dose reduction/discontinuation. ( 5.13 ) Immunizations: Avoid live vaccines. ( 5.14 ) Pure Red Cell Aplasia: Consider discontinuation of tacrolimus injection. ( 5.15 ) Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.16 ) 5.1 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including Tacrolimus Injection, are at increased 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. As usual for patients with increased risk for skin cancer, examine patients for skin changes; exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein-Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment. 5.2 Serious Infections Patients receiving immunosuppressants, including tacrolimus, are at increased 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 (PVAN), mostly due to BK virus infection JC virus-associated progressive multifocal leukoencephalopathy (PML) Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing 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 )]. 5.4 New Onset Diabetes After Transplant Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, and heart transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk.
.4 New Onset Diabetes After Transplant Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, and heart transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using tacrolimus [see Adverse Reactions ( 6.1 )] . 5.5 Nephrotoxicity due to Tacrolimus and Drug Interactions Tacrolimus, 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. Nephrotoxicity was reported in clinical trials [see Adverse Reactions ( 6.1 )]. 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 Injection 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 doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions ( 7.2 )] . 5.6 Neurotoxicity Tacrolimus 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 Injection if neurotoxicity occurs. 5.7 Hyperkalemia Hyperkalemia has been reported with tacrolimus use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during Tacrolimus therapy [see Adverse Reactions ( 6.1 )] . Monitor serum potassium levels periodically during treatment. 5.8 Hypertension Hypertension is a common adverse effect of tacrolimus therapy and may require antihypertensive therapy [see Adverse Reactions ( 6.1 )]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions ( 5.7 )] .Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of Tacrolimus [see Drug Interactions ( 7.2 )]. 5.9 Anaphylactic Reactions with Tacrolimus Injection Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus injection, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take tacrolimus orally.
mus Injection Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus injection, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take tacrolimus orally. Monitor patients for anaphylaxis when using the intravenous route of administration [see Dosage and Administration ( 2.1 )]. 5.10 Not Recommended for Use with Sirolimus Tacrolimus is not recommended for use with sirolimus: The use of sirolimus with Tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT), and is not recommended. The use of sirolimus (2 mg per day) with Tacrolimus in heart transplant patients in a U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies ( 14.3 )]. The use of sirolimus with Tacrolimus may increase the risk of thrombotic microangiopathy [see Warnings and Precautions ( 5.16 )]. 5.11 Interactions with CYP3A4 Inhibitors and Inducers When co-administering tacrolimus with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions ( 7.2 )] . 5.12 QT Prolongation Tacrolimus injection may prolong the QT/QTc interval and may cause Torsade de pointes . Avoid Tacrolimus Injection in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. When co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of tacrolimus with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions ( 7.2 )] . 5.13 Myocardial Hypertrophy Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus injection therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus injection should be considered [see Adverse Reactions ( 6.2 )] .
renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus injection therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus injection should be considered [see Adverse Reactions ( 6.2 )] . 5.14 Immunizations Whenever possible, administer the complete complement of vaccines before transplantation and treatment with tacrolimus. The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: 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 tacrolimus. 5.15 Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of tacrolimus should be considered [see Adverse Reactions ( 6.2 )] . 5.16 Thrombotic Microangiopathy (Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura) Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with tacrolimus. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA. In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA.
6 ADVERSE REACTIONS The following serious and otherwise important 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 )] New Onset Diabetes After Transplant [see Warnings and Precautions ( 5.4 )] Nephrotoxicity [see Warnings and Precautions ( 5.5 )] Neurotoxicity [see Warnings and Precautions ( 5.6 )] Hyperkalemia [see Warnings and Precautions ( 5.7 )] Hypertension [see Warnings and Precautions ( 5.8 )] Anaphylactic Reactions with Tacrolimus Injection [see Warnings and Precautions ( 5.9 )] Myocardial Hypertrophy [see Warnings and Precautions ( 5.13 )] Pure Red Cell Aplasia [see Warnings and Precautions ( 5.15 )] Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions ( 5.16 )] The most common adverse reactions (≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, Lambda Therapeutics Limited at 1-855-642-2594 or email: safety.nexuspharma@lambda-cro.com 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 Transplantation The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression. Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received tacrolimus-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on Tacrolimus and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below. The most common adverse reactions (≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.
ain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below: Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) Tacrolimus / AZA (N = 205) Cyclosporine/AZA (N = 207) Nervous System Tremor 54% 34% Headache 44% 38% Insomnia 32% 30% Paresthesia 23% 16% Dizziness 19% 16% Gastrointestinal Diarrhea 44% 41% Nausea 38% 36% Constipation 35% 43% Vomiting 29% 23% Dyspepsia 28% 20% Cardiovascular Hypertension 50% 52% Chest Pain 19% 13% Urogenital Creatinine Increased 45% 42% Urinary Tract Infection 34% 35% Metabolic and Nutritional Hypophosphatemia 49% 53% Hypomagnesemia 34% 17% Hyperlipemia 31% 38% Hyperkalemia 31% 32% Diabetes Mellitus 24% 9% Hypokalemia 22% 25% Hyperglycemia 22% 16% Edema 18% 19% Hemic and Lymphatic Anemia 30% 24% Leukopenia 15% 17% Miscellaneous Infection 45% 49% Peripheral Edema 36% 48% Asthenia 34% 30% Abdominal Pain 33% 31% Pain 32% 30% Fever 29% 29% Back Pain 24% 20% Respiratory System Dyspnea 22% 18% Cough Increased 18% 15% Musculoskeletal Arthralgia 25% 24% Skin Rash 17% 12% Pruritus 15% 7% Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n = 403), or one of two cyclosporine (CsA) regimens (Group A, n = 384 and Group B, n = 408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below: Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1) Tacrolimus (Group C) (N = 403) Cyclosporine (Group A) (N = 384) Cyclosporine (Group B) (N = 408) Diarrhea 25% 16% 13% Urinary Tract Infection 24% 28% 24% Anemia 17% 19% 17% Hypertension 13% 14% 12% Leukopenia 13% 10% 10% Edema Peripheral 11% 12% 13% Hyperlipidemia 10% 15% 13% Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil In the U.S. trial (Study 2) with Tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received Tacrolimus (n = 212) or cyclosporine (n = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below.
twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below: Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2) Tacrolimus /MMF (N = 212) Cyclosporine /MMF (N = 212) Gastrointestinal Disorders Diarrhea 44% 26% Nausea 39% 47% Constipation 36% 41% Vomiting 26% 25% Dyspepsia 18% 15% Injury, Poisoning, and Procedural Complications Post-Procedural Pain 29% 27% Incision Site Complication 28% 23% Graft Dysfunction 24% 18% Metabolism and Nutrition Disorders Hypomagnesemia 28% 22% Hypophosphatemia 28% 21% Hyperkalemia 26% 19% Hyperglycemia 21% 15% Hyperlipidemia 18% 25% Hypokalemia 16% 18% Nervous System Disorders Tremor 34% 20% Headache 24% 25% Blood and Lymphatic System Disorders Anemia 30% 28% Leukopenia 16% 12% Miscellaneous Edema Peripheral 35% 46% Hypertension 32% 35% Insomnia 30% 21% Urinary Tract Infection 26% 22% Blood Creatinine Increased 23% 23% Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.” Liver Transplantation There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70); the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%), and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%), and Other (2%). The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥ 15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation. The most common adverse reactions (≥ 40%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and intravenous administration of tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving Tacrolimus in the U.S. and European randomized trials. Table 7.
ssociated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving Tacrolimus in the U.S. and European randomized trials. Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus U.S. TRIAL EUROPEAN TRIAL Tacrolimus (N = 250) Cyclosporine/ AZA (N = 250) Tacrolimus (N = 264) Cyclosporine/ AZA (N = 265) Nervous System Headache 64% 60% 37% 26% Insomnia 64% 68% 32% 23% Tremor 56% 46% 48% 32% Paresthesia 40% 30% 17% 17% Gastrointestinal Diarrhea 72% 47% 37% 27% Nausea 46% 37% 32% 27% LFT Abnormal 36% 30% 6% 5% Anorexia 34% 24% 7% 5% Vomiting 27% 15% 14% 11% Constipation 24% 27% 23% 21% Cardiovascular Hypertension 47% 56% 38% 43% Urogenital Kidney Function Abnormal 40% 27% 36% 23% Creatinine Increased 39% 25% 24% 19% BUN Increased 30% 22% 12% 9% Oliguria 18% 15% 19% 12% Urinary Tract Infection 16% 18% 21% 19% Metabolic and Nutritional Hypomagnesemia 48% 45% 16% 9% Hyperglycemia 47% 38% 33% 22% Hyperkalemia 45% 26% 13% 9% Hypokalemia 29% 34% 13% 16% Hemic and Lymphatic Anemia 47% 38% 5% 1% Leukocytosis 32% 26% 8% 8% Thrombocytopenia 24% 20% 14% 19% Miscellaneous Pain 63% 57% 24% 22% Abdominal Pain 59% 54% 29% 22% Asthenia 52% 48% 11% 7% Fever 48% 56% 19% 22% Back Pain 30% 29% 17% 17% Ascites 27% 22% 7% 8% Peripheral Edema 26% 26% 12% 14% Respiratory System Pleural Effusion 30% 32% 36% 35% Dyspnea 29% 23% 5% 4% Atelectasis 28% 30% 5% 4% Skin and Appendages Pruritus 36% 20% 15% 7% Rash 24% 19% 10% 4% Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “ Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.” Heart Transplantation The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with Tacrolimus (n = 157) or cyclosporine (n = 157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%). The most common adverse reactions (≥ 15%) observed in tacrolimus-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial. Adverse reactions in heart transplant patients in the European trial are presented below: Table 9.
ry tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial. Adverse reactions in heart transplant patients in the European trial are presented below: Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) Tacrolimus/AZA (N = 157) Cyclosporine/AZA (N = 157) Cardiovascular System Hypertension 62% 69% Pericardial Effusion 15% 14% Body as a Whole CMV Infection 32% 30% Infection 24% 21% Metabolic and Nutritional Disorders Diabetes Mellitus 26% 16% Hyperglycemia 23% 17% Hyperlipemia 18% 27% Hemic and Lymphatic System Anemia 50% 36% Leukopenia 48% 39% Urogenital System Kidney Function Abnormal 56% 57% Urinary Tract Infection 16% 12% Respiratory System Bronchitis 17% 18% Nervous System Tremor 15% 6% In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 nanogram/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 nanogram/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and tacrolimus in combination with sirolimus (n=109), tacrolimus in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%). Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with tacrolimus and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%) , hypertriglyceridemia (65%), anemia (hemoglobin < 10.0 g/dL) (65%), fasting blood glucose > 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs < 3000 cells/mcL (34%), serious bacterial infections (30%), magnesium < 1.2 mEq/L (24%), platelet count < 75,000 cells/mcL (19%), and other opportunistic infections (15%). Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.” New Onset Diabetes After Transplant Kidney Transplantation New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥ 126 mg/dL, HbA 1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the Tacrolimus-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus ( Table 10 ) [see Clinical Studies ( 14.1 )] . Table 10.
mg/dL, HbA 1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the Tacrolimus-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus ( Table 10 ) [see Clinical Studies ( 14.1 )] . Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2) Parameter Treatment Group Tacrolimus/ MMF (N = 212) NEORAL/MMF (N = 212) NODAT 112/150 (75%) 93/152 (61%) Fasting Plasma Glucose ≥ 126 mg/dL 96/150 (64%) 80/152 (53%) HbA 1C ≥ 6% 59/150 (39%) 28/152 (18%) Insulin Use ≥ 30 days 9/150 (6%) 4/152 (3%) Oral Hypoglycemic Use 15/150 (10%) 5/152 (3%) In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of “use of insulin for 30 or more consecutive days with < 5-day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14 . PTDM was reported in 20% of Tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial ( Table 11 ). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM ( Table 12 ). Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA) * Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus. Status of PTDM * Tacrolimus/AZA CsA/AZA Patients without pre-transplant history of diabetes mellitus 151 151 New onset PTDM * , 1 st Year 30/151 (20%) 6/151 (4%) Still insulin-dependent at one year in those without prior history of diabetes 25/151 (17%) 5/151 (3%) New onset PTDM * post 1 year 1 0 Patients with PTDM * at 2 years 16/151 (11%) 5/151 (3%) Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial *Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus. Patient Race Patients Who Developed PTDM * Tacrolimus Cyclosporine African-American 15/41 (37%) 3 (8%) Hispanic 5/17 (29%) 1 (6%) Caucasian 10/82 (12%) 1 (1%) Other 0/11 (0%) 1 (10%) Total 30/151 (20%) 6 (4%) Liver Transplantation Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively ( Table 13 ). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions ( 6.1 )]. Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients 1. Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus. 2. Patients without pre-transplant history of diabetes mellitus.
ant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients 1. Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus. 2. Patients without pre-transplant history of diabetes mellitus. Status of PTDM 1 US Trial European Trial Tacrolimus Cyclosporine Tacrolimus Cyclosporine Patients at risk 2 239 236 239 249 New Onset PTDM 1 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) Heart Transplantation Insulin-dependent PTDM was reported in 13% and 22% of tacrolimus-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively ( Table 14 ). Hyperglycemia, defined as two fasting plasma glucose levels ≥ 126 mg/dL, was reported with the use of Tacrolimus plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions ( 6.1 )]. Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients 1. Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. 2. Patients without pre-transplant history of diabetes mellitus. 3. 7-12 months for the U.S. trial. Status of PTDM 1 US Trial European Trial Tacrolimus/MMF Cyclosporine/MMF Tacrolimus/AZA Cyclosporine/AZA Patients at risk 2 75 83 132 138 New Onset PTDM 1 10 (13%) 6 (7%) 29 (22%) 5 (4%) Patients still on insulin at 1 year 3 7 (9%) 1 (1%) 24 (18%) 4 (3%) Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.
l on insulin at 1 year 3 7 (9%) 1 (1%) 24 (18%) 4 (3%) Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials. Nervous System: Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired Special Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitus Gastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation Urogenital: Acute kidney failure , albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis Metabolic/Nutritional: Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gain Endocrine: Cushing's syndrome Hemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration Skin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweating Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf ® (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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.
ing Experience The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug. Other reactions include: Cardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsade de Pointes , venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia, thrombotic microangiopathy Infections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; polyoma virus- associated nephropathy (PVAN) including graft loss Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased Miscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) Nervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope Respiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis Special Senses: Blindness, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome
<table ID="t4" width="100%"><caption>Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)</caption><col width="28.533%" align="left"/><col width="35.733%" align="left"/><col width="35.733%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td align="left" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Tacrolimus / AZA (N = 205)</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Cyclosporine/AZA (N = 207)</content></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Nervous System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Tremor</td><td align="left" styleCode="Botrule Rrule" valign="middle">54%</td><td align="left" styleCode="Botrule Rrule" valign="middle">34%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Headache</td><td align="left" styleCode="Botrule Rrule" valign="middle">44%</td><td align="left" styleCode="Botrule Rrule" valign="middle">38%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Insomnia</td><td align="left" styleCode="Botrule Rrule" valign="middle">32%</td><td align="left" styleCode="Botrule Rrule" valign="middle">30%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Paresthesia</td><td align="left" styleCode="Botrule Rrule" valign="middle">23%</td><td align="left" styleCode="Botrule Rrule" valign="middle">16%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Dizziness</td><td align="left" styleCode="Botrule Rrule" valign="middle">19%</td><td align="left" styleCode="Botrule Rrule" valign="middle">16%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Gastrointestinal</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Diarrhea</td><td align="left" styleCode="Botrule Rrule" valign="middle">44%</td><td align="left" styleCode="Botrule Rrule" valign="middle">41%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Nausea</td><td align="left" styleCode="Botrule Rrule" valign="middle">38%</td><td align="left" styleCode="Botrule Rrule" valign="middle">36%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Constipation</td><td align="left" styleCode="Botrule Rrule" valign="middle">35%</td><td align="left" styleCode="Botrule Rrule" valign="middle">43%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Vomiting</td><td align="left" styleCode="Botrule Rrule" valign="middle">29%</td><td align="left" styleCode="Botrule Rrule" valign="middle">23%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Dyspepsia</td><td align="left" styleCode="Botrule Rrule" valign="middle">28%</td><td align="left" styleCode="Botrule Rrule" valign="middle">20%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Cardiovascular</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Hypertension</td><td align="left" styleCode="Botrule Rrule" valign="middle">50%</td><td align="left" styleCode="Botrule Rrule" valign="middle">52%</td></tr><tr><td align="left" styleCode="
p"><content styleCode="bold">Cardiovascular</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Hypertension</td><td align="left" styleCode="Botrule Rrule" valign="middle">50%</td><td align="left" styleCode="Botrule Rrule" valign="middle">52%</td></tr><tr><td align="left" styleCode=" Botrule Lrule Rrule" valign="middle">Chest Pain</td><td align="left" styleCode="Botrule Rrule" valign="middle">19%</td><td align="left" styleCode="Botrule Rrule" valign="middle">13%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Urogenital</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Creatinine Increased</td><td align="left" styleCode="Botrule Rrule" valign="middle">45%</td><td align="left" styleCode="Botrule Rrule" valign="middle">42%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Urinary Tract Infection</td><td align="left" styleCode="Botrule Rrule" valign="middle">34%</td><td align="left" styleCode="Botrule Rrule" valign="middle">35%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Metabolic and Nutritional</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Hypophosphatemia</td><td align="left" styleCode="Botrule Rrule" valign="middle">49%</td><td align="left" styleCode="Botrule Rrule" valign="middle">53%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Hypomagnesemia</td><td align="left" styleCode="Botrule Rrule" valign="middle">34%</td><td align="left" styleCode="Botrule Rrule" valign="middle">17%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Hyperlipemia</td><td align="left" styleCode="Botrule Rrule" valign="middle">31%</td><td align="left" styleCode="Botrule Rrule" valign="middle">38%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Hyperkalemia</td><td align="left" styleCode="Botrule Rrule" valign="middle">31%</td><td align="left" styleCode="Botrule Rrule" valign="middle">32%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Diabetes Mellitus</td><td align="left" styleCode="Botrule Rrule" valign="middle">24%</td><td align="left" styleCode="Botrule Rrule" valign="middle">9%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Hypokalemia</td><td align="left" styleCode="Botrule Rrule" valign="middle">22%</td><td align="left" styleCode="Botrule Rrule" valign="middle">25%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Hyperglycemia</td><td align="left" styleCode="Botrule Rrule" valign="middle">22%</td><td align="left" styleCode="Botrule Rrule" valign="middle">16%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Edema</td><td align="left" styleCode="Botrule Rrule" valign="middle">18%</td><td align="left" styleCode="Botrule Rrule" valign="middle">19%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Hemic and Lymphatic</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Anemia</td><td align="left" styleCode="Botrule Rrule" valign="middle">30%</td><td align="left" styleCode="Botrule Rrule" valign="middle">24%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Leukopenia</td><td align="left" styleCode="Botrule Rrule" valign="middle">15%</td><td align="left" styleCode="Botrule Rrule" valign="middle">17%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Miscellaneous</content></td></tr><tr><td align="left" style
e">Leukopenia</td><td align="left" styleCode="Botrule Rrule" valign="middle">15%</td><td align="left" styleCode="Botrule Rrule" valign="middle">17%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Miscellaneous</content></td></tr><tr><td align="left" style Code="Botrule Lrule Rrule" valign="middle">Infection</td><td align="left" styleCode="Botrule Rrule" valign="middle">45%</td><td align="left" styleCode="Botrule Rrule" valign="middle">49%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Peripheral Edema</td><td align="left" styleCode="Botrule Rrule" valign="middle">36%</td><td align="left" styleCode="Botrule Rrule" valign="middle">48%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Asthenia</td><td align="left" styleCode="Botrule Rrule" valign="middle">34%</td><td align="left" styleCode="Botrule Rrule" valign="middle">30%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Abdominal Pain</td><td align="left" styleCode="Botrule Rrule" valign="middle">33%</td><td align="left" styleCode="Botrule Rrule" valign="middle">31%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Pain</td><td align="left" styleCode="Botrule Rrule" valign="middle">32%</td><td align="left" styleCode="Botrule Rrule" valign="middle">30%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Fever</td><td align="left" styleCode="Botrule Rrule" valign="middle">29%</td><td align="left" styleCode="Botrule Rrule" valign="middle">29%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Back Pain</td><td align="left" styleCode="Botrule Rrule" valign="middle">24%</td><td align="left" styleCode="Botrule Rrule" valign="middle">20%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Respiratory System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Dyspnea</td><td align="left" styleCode="Botrule Rrule" valign="middle">22%</td><td align="left" styleCode="Botrule Rrule" valign="middle">18%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Cough Increased</td><td align="left" styleCode="Botrule Rrule" valign="middle">18%</td><td align="left" styleCode="Botrule Rrule" valign="middle">15%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Musculoskeletal</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Arthralgia</td><td align="left" styleCode="Botrule Rrule" valign="middle">25%</td><td align="left" styleCode="Botrule Rrule" valign="middle">24%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Skin</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Rash</td><td align="left" styleCode="Botrule Rrule" valign="middle">17%</td><td align="left" styleCode="Botrule Rrule" valign="middle">12%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Pruritus</td><td align="left" styleCode="Botrule Rrule" valign="middle">15%</td><td align="left" styleCode="Botrule Rrule" valign="middle">7%</td></tr></tbody></table>
le">17%</td><td align="left" styleCode="Botrule Rrule" valign="middle">12%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Pruritus</td><td align="left" styleCode="Botrule Rrule" valign="middle">15%</td><td align="left" styleCode="Botrule Rrule" valign="middle">7%</td></tr></tbody></table> <table ID="t5" width="100%"><caption>Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)</caption><col width="18.775%" align="left"/><col width="27.075%" align="left"/><col width="27.075%" align="left"/><col width="27.075%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus (Group C)</content> <content styleCode="bold">(N = 403)</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine (Group A)</content> <content styleCode="bold">(N = 384)</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine (Group B)</content> <content styleCode="bold">(N = 408)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Diarrhea</td><td align="left" styleCode="Botrule Rrule" valign="top">25%</td><td align="left" styleCode="Botrule Rrule" valign="top">16%</td><td align="left" styleCode="Botrule Rrule" valign="top">13%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Urinary Tract Infection</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">28%</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Anemia</td><td align="left" styleCode="Botrule Rrule" valign="top">17%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td><td align="left" styleCode="Botrule Rrule" valign="top">17%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hypertension</td><td align="left" styleCode="Botrule Rrule" valign="top">13%</td><td align="left" styleCode="Botrule Rrule" valign="top">14%</td><td align="left" styleCode="Botrule Rrule" valign="top">12%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Leukopenia</td><td align="left" styleCode="Botrule Rrule" valign="top">13%</td><td align="left" styleCode="Botrule Rrule" valign="top">10%</td><td align="left" styleCode="Botrule Rrule" valign="top">10%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Edema Peripheral</td><td align="left" styleCode="Botrule Rrule" valign="top">11%</td><td align="left" styleCode="Botrule Rrule" valign="top">12%</td><td align="left" styleCode="Botrule Rrule" valign="top">13%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hyperlipidemia</td><td align="left" styleCode="Botrule Rrule" valign="top">10%</td><td align="left" styleCode="Botrule Rrule" valign="top">15%</td><td align="left" styleCode="Botrule Rrule" valign="top">13%</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil</content></td></tr></tbody></table>
13%</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil</content></td></tr></tbody></table> <table ID="t6" width="100%"><caption>Table 6.
13%</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil</content></td></tr></tbody></table> <table ID="t6" width="100%"><caption>Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)</caption><col width="22.000%" align="left"/><col width="39.000%" align="left"/><col width="39.000%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus /MMF</content> <content styleCode="bold">(N = 212)</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine</content> <content styleCode="bold">/MMF</content> <content styleCode="bold">(N = 212)</content></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Diarrhea</td><td align="left" styleCode="Botrule Rrule" valign="top">44%</td><td align="left" styleCode="Botrule Rrule" valign="top">26%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Nausea</td><td align="left" styleCode="Botrule Rrule" valign="top">39%</td><td align="left" styleCode="Botrule Rrule" valign="top">47%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Constipation</td><td align="left" styleCode="Botrule Rrule" valign="top">36%</td><td align="left" styleCode="Botrule Rrule" valign="top">41%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Vomiting</td><td align="left" styleCode="Botrule Rrule" valign="top">26%</td><td align="left" styleCode="Botrule Rrule" valign="top">25%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Dyspepsia</td><td align="left" styleCode="Botrule Rrule" valign="top">18%</td><td align="left" styleCode="Botrule Rrule" valign="top">15%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Injury, Poisoning, and Procedural Complications</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Post-Procedural Pain</td><td align="left" styleCode="Botrule Rrule" valign="top">29%</td><td align="left" styleCode="Botrule Rrule" valign="top">27%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Incision Site Complication</td><td align="left" styleCode="Botrule Rrule" valign="top">28%</td><td align="left" styleCode="Botrule Rrule" valign="top">23%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Graft Dysfunction</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">18%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hypomagnesemia</td><td align="left" styleCode="Botrule Rrule" valign="top">28%</td><td align="left" styleCode="Botrule Rrule" valign="top">22%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hypophosphatemia</td><td align="left" styleCode="Botrule Rrule" valign="top">28%</td><td align="left" styleCode="Botrule Rrule" valign="top">21%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hyperkalemia</td><td align="left" styleCode="Botrule Rrule" valign="to
ule Lrule Rrule" valign="top">Hypophosphatemia</td><td align="left" styleCode="Botrule Rrule" valign="top">28%</td><td align="left" styleCode="Botrule Rrule" valign="top">21%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hyperkalemia</td><td align="left" styleCode="Botrule Rrule" valign="to p">26%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hyperglycemia</td><td align="left" styleCode="Botrule Rrule" valign="top">21%</td><td align="left" styleCode="Botrule Rrule" valign="top">15%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hyperlipidemia</td><td align="left" styleCode="Botrule Rrule" valign="top">18%</td><td align="left" styleCode="Botrule Rrule" valign="top">25%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hypokalemia</td><td align="left" styleCode="Botrule Rrule" valign="top">16%</td><td align="left" styleCode="Botrule Rrule" valign="top">18%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Tremor</td><td align="left" styleCode="Botrule Rrule" valign="top">34%</td><td align="left" styleCode="Botrule Rrule" valign="top">20%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Headache</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">25%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Blood and Lymphatic System Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Anemia</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td><td align="left" styleCode="Botrule Rrule" valign="top">28%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Leukopenia</td><td align="left" styleCode="Botrule Rrule" valign="top">16%</td><td align="left" styleCode="Botrule Rrule" valign="top">12%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Miscellaneous</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Edema Peripheral</td><td align="left" styleCode="Botrule Rrule" valign="top">35%</td><td align="left" styleCode="Botrule Rrule" valign="top">46%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hypertension</td><td align="left" styleCode="Botrule Rrule" valign="top">32%</td><td align="left" styleCode="Botrule Rrule" valign="top">35%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Insomnia</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td><td align="left" styleCode="Botrule Rrule" valign="top">21%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Urinary Tract Infection</td><td align="left" styleCode="Botrule Rrule" valign="top">26%</td><td align="left" styleCode="Botrule Rrule" valign="top">22%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Blood Creatinine Increased</td><td align="left" styleCode="Botrule Rrule" valign="top">23%</td><td align="left" styleCode="Botrule Rrule" valign="top">23%</td></tr></tbody></table>
</td><td align="left" styleCode="Botrule Rrule" valign="top">22%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Blood Creatinine Increased</td><td align="left" styleCode="Botrule Rrule" valign="top">23%</td><td align="left" styleCode="Botrule Rrule" valign="top">23%</td></tr></tbody></table> <table ID="t7" width="100%"><caption>Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus</caption><col width="29.626%" align="left"/><col width="17.584%" align="left"/><col width="17.604%" align="left"/><col width="17.584%" align="left"/><col width="17.604%" align="left"/><tbody><tr><td rowspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td colspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">U.S.
align="left"/><col width="17.604%" align="left"/><col width="17.584%" align="left"/><col width="17.604%" align="left"/><tbody><tr><td rowspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td colspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">U.S. TRIAL</content></td><td colspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">EUROPEAN TRIAL</content></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus</content> <content styleCode="bold">(N = 250)</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine/ AZA</content> <content styleCode="bold">(N = 250)</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus</content> <content styleCode="bold">(N = 264)</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine/ AZA</content> <content styleCode="bold">(N = 265)</content></td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Nervous System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Headache</td><td align="left" styleCode="Botrule Rrule" valign="top">64%</td><td align="left" styleCode="Botrule Rrule" valign="top">60%</td><td align="left" styleCode="Botrule Rrule" valign="top">37%</td><td align="left" styleCode="Botrule Rrule" valign="top">26%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Insomnia</td><td align="left" styleCode="Botrule Rrule" valign="top">64%</td><td align="left" styleCode="Botrule Rrule" valign="top">68%</td><td align="left" styleCode="Botrule Rrule" valign="top">32%</td><td align="left" styleCode="Botrule Rrule" valign="top">23%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Tremor</td><td align="left" styleCode="Botrule Rrule" valign="top">56%</td><td align="left" styleCode="Botrule Rrule" valign="top">46%</td><td align="left" styleCode="Botrule Rrule" valign="top">48%</td><td align="left" styleCode="Botrule Rrule" valign="top">32%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Paresthesia</td><td align="left" styleCode="Botrule Rrule" valign="top">40%</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td><td align="left" styleCode="Botrule Rrule" valign="top">17%</td><td align="left" styleCode="Botrule Rrule" valign="top">17%</td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Gastrointestinal</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Diarrhea</td><td align="left" styleCode="Botrule Rrule" valign="top">72%</td><td align="left" styleCode="Botrule Rrule" valign="top">47%</td><td align="left" styleCode="Botrule Rrule" valign="top">37%</td><td align="left" styleCode="Botrule Rrule" valign="top">27%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Nausea</td><td align="left" styleCode="Botrule Rrule" valign="top">46%</td><td align="left" styleCode="Botrule Rrule" valign="top">37%</td><td align="left" styleCode="Botrule Rrule" valign="top">32%</td><td align="left" styleCode="Botrule Rrule" valign="top">27%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">LFT Abnormal</td><td align="left" styleCode="Botrule Rrule" valign="top">36%</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td><td align="left" styleCode="Botrule Rrule" valign="top">6%</td><td align="left" styleCode="Botrule Rrule" valign="top">5%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrul
normal</td><td align="left" styleCode="Botrule Rrule" valign="top">36%</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td><td align="left" styleCode="Botrule Rrule" valign="top">6%</td><td align="left" styleCode="Botrule Rrule" valign="top">5%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrul e" valign="top">Anorexia</td><td align="left" styleCode="Botrule Rrule" valign="top">34%</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">7%</td><td align="left" styleCode="Botrule Rrule" valign="top">5%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Vomiting</td><td align="left" styleCode="Botrule Rrule" valign="top">27%</td><td align="left" styleCode="Botrule Rrule" valign="top">15%</td><td align="left" styleCode="Botrule Rrule" valign="top">14%</td><td align="left" styleCode="Botrule Rrule" valign="top">11%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Constipation</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">27%</td><td align="left" styleCode="Botrule Rrule" valign="top">23%</td><td align="left" styleCode="Botrule Rrule" valign="top">21%</td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Cardiovascular</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hypertension</td><td align="left" styleCode="Botrule Rrule" valign="top">47%</td><td align="left" styleCode="Botrule Rrule" valign="top">56%</td><td align="left" styleCode="Botrule Rrule" valign="top">38%</td><td align="left" styleCode="Botrule Rrule" valign="top">43%</td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Urogenital</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Kidney Function Abnormal</td><td align="left" styleCode="Botrule Rrule" valign="top">40%</td><td align="left" styleCode="Botrule Rrule" valign="top">27%</td><td align="left" styleCode="Botrule Rrule" valign="top">36%</td><td align="left" styleCode="Botrule Rrule" valign="top">23%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Creatinine Increased</td><td align="left" styleCode="Botrule Rrule" valign="top">39%</td><td align="left" styleCode="Botrule Rrule" valign="top">25%</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">BUN Increased</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td><td align="left" styleCode="Botrule Rrule" valign="top">22%</td><td align="left" styleCode="Botrule Rrule" valign="top">12%</td><td align="left" styleCode="Botrule Rrule" valign="top">9%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Oliguria</td><td align="left" styleCode="Botrule Rrule" valign="top">18%</td><td align="left" styleCode="Botrule Rrule" valign="top">15%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td><td align="left" styleCode="Botrule Rrule" valign="top">12%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Urinary Tract Infection</td><td align="left" styleCode="Botrule Rrule" valign="top">16%</td><td align="left" styleCode="Botrule Rrule" valign="top">18%</td><td align="left" styleCode="Botrule Rrule" valign="top">21%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Metabolic and Nutritional</content></td></tr><tr><td align="l
valign="top">18%</td><td align="left" styleCode="Botrule Rrule" valign="top">21%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Metabolic and Nutritional</content></td></tr><tr><td align="l eft" styleCode="Botrule Lrule Rrule" valign="top">Hypomagnesemia</td><td align="left" styleCode="Botrule Rrule" valign="top">48%</td><td align="left" styleCode="Botrule Rrule" valign="top">45%</td><td align="left" styleCode="Botrule Rrule" valign="top">16%</td><td align="left" styleCode="Botrule Rrule" valign="top">9%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hyperglycemia</td><td align="left" styleCode="Botrule Rrule" valign="top">47%</td><td align="left" styleCode="Botrule Rrule" valign="top">38%</td><td align="left" styleCode="Botrule Rrule" valign="top">33%</td><td align="left" styleCode="Botrule Rrule" valign="top">22%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hyperkalemia</td><td align="left" styleCode="Botrule Rrule" valign="top">45%</td><td align="left" styleCode="Botrule Rrule" valign="top">26%</td><td align="left" styleCode="Botrule Rrule" valign="top">13%</td><td align="left" styleCode="Botrule Rrule" valign="top">9%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hypokalemia</td><td align="left" styleCode="Botrule Rrule" valign="top">29%</td><td align="left" styleCode="Botrule Rrule" valign="top">34%</td><td align="left" styleCode="Botrule Rrule" valign="top">13%</td><td align="left" styleCode="Botrule Rrule" valign="top">16%</td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Hemic and Lymphatic</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Anemia</td><td align="left" styleCode="Botrule Rrule" valign="top">47%</td><td align="left" styleCode="Botrule Rrule" valign="top">38%</td><td align="left" styleCode="Botrule Rrule" valign="top">5%</td><td align="left" styleCode="Botrule Rrule" valign="top">1%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Leukocytosis</td><td align="left" styleCode="Botrule Rrule" valign="top">32%</td><td align="left" styleCode="Botrule Rrule" valign="top">26%</td><td align="left" styleCode="Botrule Rrule" valign="top">8%</td><td align="left" styleCode="Botrule Rrule" valign="top">8%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Thrombocytopenia</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">20%</td><td align="left" styleCode="Botrule Rrule" valign="top">14%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Miscellaneous</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Pain</td><td align="left" styleCode="Botrule Rrule" valign="top">63%</td><td align="left" styleCode="Botrule Rrule" valign="top">57%</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">22%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Abdominal Pain</td><td align="left" styleCode="Botrule Rrule" valign="top">59%</td><td align="left" styleCode="Botrule Rrule" valign="top">54%</td><td align="left" styleCode="Botrule Rrule" valign="top">29%</td><td align="left" styleCode="Botrule Rrule" valign="top">22%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Asthenia</td><td align="left" styleCode="Botrule Rrule" valign="top">52%</td><td align
otrule Rrule" valign="top">54%</td><td align="left" styleCode="Botrule Rrule" valign="top">29%</td><td align="left" styleCode="Botrule Rrule" valign="top">22%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Asthenia</td><td align="left" styleCode="Botrule Rrule" valign="top">52%</td><td align ="left" styleCode="Botrule Rrule" valign="top">48%</td><td align="left" styleCode="Botrule Rrule" valign="top">11%</td><td align="left" styleCode="Botrule Rrule" valign="top">7%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Fever</td><td align="left" styleCode="Botrule Rrule" valign="top">48%</td><td align="left" styleCode="Botrule Rrule" valign="top">56%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td><td align="left" styleCode="Botrule Rrule" valign="top">22%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Back Pain</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td><td align="left" styleCode="Botrule Rrule" valign="top">29%</td><td align="left" styleCode="Botrule Rrule" valign="top">17%</td><td align="left" styleCode="Botrule Rrule" valign="top">17%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Ascites</td><td align="left" styleCode="Botrule Rrule" valign="top">27%</td><td align="left" styleCode="Botrule Rrule" valign="top">22%</td><td align="left" styleCode="Botrule Rrule" valign="top">7%</td><td align="left" styleCode="Botrule Rrule" valign="top">8%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Peripheral Edema</td><td align="left" styleCode="Botrule Rrule" valign="top">26%</td><td align="left" styleCode="Botrule Rrule" valign="top">26%</td><td align="left" styleCode="Botrule Rrule" valign="top">12%</td><td align="left" styleCode="Botrule Rrule" valign="top">14%</td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Respiratory System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Pleural Effusion</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td><td align="left" styleCode="Botrule Rrule" valign="top">32%</td><td align="left" styleCode="Botrule Rrule" valign="top">36%</td><td align="left" styleCode="Botrule Rrule" valign="top">35%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Dyspnea</td><td align="left" styleCode="Botrule Rrule" valign="top">29%</td><td align="left" styleCode="Botrule Rrule" valign="top">23%</td><td align="left" styleCode="Botrule Rrule" valign="top">5%</td><td align="left" styleCode="Botrule Rrule" valign="top">4%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Atelectasis</td><td align="left" styleCode="Botrule Rrule" valign="top">28%</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td><td align="left" styleCode="Botrule Rrule" valign="top">5%</td><td align="left" styleCode="Botrule Rrule" valign="top">4%</td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Skin and Appendages</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Pruritus</td><td align="left" styleCode="Botrule Rrule" valign="top">36%</td><td align="left" styleCode="Botrule Rrule" valign="top">20%</td><td align="left" styleCode="Botrule Rrule" valign="top">15%</td><td align="left" styleCode="Botrule Rrule" valign="top">7%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Rash</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td><td align="left" styleCode="Botrule Rrule" valign="top">10%</td><td align="left" styleCode="Botru
n="top">7%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Rash</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td><td align="left" styleCode="Botrule Rrule" valign="top">10%</td><td align="left" styleCode="Botru le Rrule" valign="top">4%</td></tr></tbody></table> <table ID="t9" width="100%"><caption>Table 9.
n="top">7%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Rash</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">19%</td><td align="left" styleCode="Botrule Rrule" valign="top">10%</td><td align="left" styleCode="Botru le Rrule" valign="top">4%</td></tr></tbody></table> <table ID="t9" width="100%"><caption>Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)</caption><col width="23.700%" align="left"/><col width="38.567%" align="left"/><col width="37.733%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus/AZA</content> <content styleCode="bold">(N = 157)</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N = 157)</content></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Cardiovascular System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hypertension</td><td align="left" styleCode="Botrule Rrule" valign="top">62%</td><td align="left" styleCode="Botrule Rrule" valign="top">69%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Pericardial Effusion</td><td align="left" styleCode="Botrule Rrule" valign="top">15%</td><td align="left" styleCode="Botrule Rrule" valign="top">14%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Body as a Whole</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">CMV Infection</td><td align="left" styleCode="Botrule Rrule" valign="top">32%</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Infection</td><td align="left" styleCode="Botrule Rrule" valign="top">24%</td><td align="left" styleCode="Botrule Rrule" valign="top">21%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Diabetes Mellitus</td><td align="left" styleCode="Botrule Rrule" valign="top">26%</td><td align="left" styleCode="Botrule Rrule" valign="top">16%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hyperglycemia</td><td align="left" styleCode="Botrule Rrule" valign="top">23%</td><td align="left" styleCode="Botrule Rrule" valign="top">17%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hyperlipemia</td><td align="left" styleCode="Botrule Rrule" valign="top">18%</td><td align="left" styleCode="Botrule Rrule" valign="top">27%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Hemic and Lymphatic System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Anemia</td><td align="left" styleCode="Botrule Rrule" valign="top">50%</td><td align="left" styleCode="Botrule Rrule" valign="top">36%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Leukopenia</td><td align="left" styleCode="Botrule Rrule" valign="top">48%</td><td align="left" styleCode="Botrule Rrule" valign="top">39%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Urogenital System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Kidney Function Abnormal</td><td align="left" styleCode="Botrule Rrule" valig
le Rrule" valign="top">39%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Urogenital System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Kidney Function Abnormal</td><td align="left" styleCode="Botrule Rrule" valig n="top">56%</td><td align="left" styleCode="Botrule Rrule" valign="top">57%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Urinary Tract Infection</td><td align="left" styleCode="Botrule Rrule" valign="top">16%</td><td align="left" styleCode="Botrule Rrule" valign="top">12%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Respiratory System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Bronchitis</td><td align="left" styleCode="Botrule Rrule" valign="top">17%</td><td align="left" styleCode="Botrule Rrule" valign="top">18%</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Nervous System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Tremor</td><td align="left" styleCode="Botrule Rrule" valign="top">15%</td><td align="left" styleCode="Botrule Rrule" valign="top">6%</td></tr></tbody></table>
"Botrule Lrule Rrule" valign="top"><content styleCode="bold">Nervous System</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Tremor</td><td align="left" styleCode="Botrule Rrule" valign="top">15%</td><td align="left" styleCode="Botrule Rrule" valign="top">6%</td></tr></tbody></table> <table ID="t10" width="100%"><caption>Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)</caption><col width="38.954%" align="left"/><col width="30.523%" align="left"/><col width="30.523%" align="left"/><tbody><tr><td rowspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Parameter</content></td><td colspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Treatment Group</content></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus/</content> <content styleCode="bold">MMF</content> <content styleCode="bold">(N = 212)</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">NEORAL/MMF</content> <content styleCode="bold">(N = 212)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">NODAT</td><td align="left" styleCode="Botrule Rrule" valign="top">112/150 (75%)</td><td align="left" styleCode="Botrule Rrule" valign="top">93/152 (61%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Fasting Plasma Glucose ≥ 126 mg/dL</td><td align="left" styleCode="Botrule Rrule" valign="top">96/150 (64%)</td><td align="left" styleCode="Botrule Rrule" valign="top">80/152 (53%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">HbA <sub>1C</sub>≥ 6% </td><td align="left" styleCode="Botrule Rrule" valign="top">59/150 (39%)</td><td align="left" styleCode="Botrule Rrule" valign="top">28/152 (18%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Insulin Use ≥ 30 days</td><td align="left" styleCode="Botrule Rrule" valign="top">9/150 (6%)</td><td align="left" styleCode="Botrule Rrule" valign="top">4/152 (3%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Oral Hypoglycemic Use</td><td align="left" styleCode="Botrule Rrule" valign="top">15/150 (10%)</td><td align="left" styleCode="Botrule Rrule" valign="top">5/152 (3%)</td></tr></tbody></table>
ft" styleCode="Botrule Rrule" valign="top">4/152 (3%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Oral Hypoglycemic Use</td><td align="left" styleCode="Botrule Rrule" valign="top">15/150 (10%)</td><td align="left" styleCode="Botrule Rrule" valign="top">5/152 (3%)</td></tr></tbody></table> <table ID="t11" width="100%"><caption>Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)</caption><col width="33.333%" align="left"/><col width="33.333%" align="left"/><col width="33.333%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><content styleCode="bold">*</content>Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus. </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Status of PTDM</content><content styleCode="bold"><content styleCode="italics"><sup>*</sup></content></content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus/AZA</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">CsA/AZA</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Patients without pre-transplant history of diabetes mellitus</td><td align="left" styleCode="Botrule Rrule" valign="top">151</td><td align="left" styleCode="Botrule Rrule" valign="top">151</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">New onset PTDM <content styleCode="italics"><sup>*</sup></content>, 1 <sup>st</sup>Year </td><td align="left" styleCode="Botrule Rrule" valign="top">30/151 (20%)</td><td align="left" styleCode="Botrule Rrule" valign="top">6/151 (4%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Still insulin-dependent at one year in those without prior history of diabetes</td><td align="left" styleCode="Botrule Rrule" valign="top">25/151 (17%)</td><td align="left" styleCode="Botrule Rrule" valign="top">5/151 (3%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">New onset PTDM <content styleCode="italics"><sup>*</sup></content>post 1 year </td><td align="left" styleCode="Botrule Rrule" valign="top">1</td><td align="left" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Patients with PTDM <sup>*</sup>at 2 years </td><td align="left" styleCode="Botrule Rrule" valign="top">16/151 (11%)</td><td align="left" styleCode="Botrule Rrule" valign="top">5/151 (3%)</td></tr></tbody></table>
e="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Patients with PTDM <sup>*</sup>at 2 years </td><td align="left" styleCode="Botrule Rrule" valign="top">16/151 (11%)</td><td align="left" styleCode="Botrule Rrule" valign="top">5/151 (3%)</td></tr></tbody></table> <table ID="t12" width="100%"><caption>Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial</caption><col width="18.760%" align="left"/><col width="40.620%" align="left"/><col width="40.620%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">*Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus.</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Patient Race</content></td><td colspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Patients Who Developed PTDM</content><content styleCode="bold"><content styleCode="italics"><sup>*</sup></content></content></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">African-American</td><td align="left" styleCode="Botrule Rrule" valign="top">15/41 (37%)</td><td align="left" styleCode="Botrule Rrule" valign="top">3 (8%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Hispanic</td><td align="left" styleCode="Botrule Rrule" valign="top">5/17 (29%)</td><td align="left" styleCode="Botrule Rrule" valign="top">1 (6%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Caucasian</td><td align="left" styleCode="Botrule Rrule" valign="top">10/82 (12%)</td><td align="left" styleCode="Botrule Rrule" valign="top">1 (1%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Other</td><td align="left" styleCode="Botrule Rrule" valign="top">0/11 (0%)</td><td align="left" styleCode="Botrule Rrule" valign="top">1 (10%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Total</td><td align="left" styleCode="Botrule Rrule" valign="top">30/151 (20%)</td><td align="left" styleCode="Botrule Rrule" valign="top">6 (4%)</td></tr></tbody></table>
(0%)</td><td align="left" styleCode="Botrule Rrule" valign="top">1 (10%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Total</td><td align="left" styleCode="Botrule Rrule" valign="top">30/151 (20%)</td><td align="left" styleCode="Botrule Rrule" valign="top">6 (4%)</td></tr></tbody></table> <table ID="t13" width="100%"><caption>Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients</caption><col width="27.091%" align="left"/><col width="18.227%" align="left"/><col width="18.227%" align="left"/><col width="18.227%" align="left"/><col width="18.227%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">1. Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non- insulin dependent diabetes mellitus.</paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">2. Patients without pre-transplant history of diabetes mellitus.</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Status of PTDM</content><content styleCode="bold"><sup>1</sup></content></td><td colspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">US Trial</content></td><td colspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">European Trial</content></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Patients at risk <sup>2</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">239</td><td align="left" styleCode="Botrule Rrule" valign="top">236</td><td align="left" styleCode="Botrule Rrule" valign="top">239</td><td align="left" styleCode="Botrule Rrule" valign="top">249</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">New Onset PTDM <sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">42 (18%)</td><td align="left" styleCode="Botrule Rrule" valign="top">30 (13%)</td><td align="left" styleCode="Botrule Rrule" valign="top">26 (11%)</td><td align="left" styleCode="Botrule Rrule" valign="top">12 (5%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Patients still on insulin at 1 year</td><td align="left" styleCode="Botrule Rrule" valign="top">23 (10%)</td><td align="left" styleCode="Botrule Rrule" valign="top">19 (8%)</td><td align="left" styleCode="Botrule Rrule" valign="top">18 (8%)</td><td align="left" styleCode="Botrule Rrule" valign="top">6 (2%)</td></tr></tbody></table>
l on insulin at 1 year</td><td align="left" styleCode="Botrule Rrule" valign="top">23 (10%)</td><td align="left" styleCode="Botrule Rrule" valign="top">19 (8%)</td><td align="left" styleCode="Botrule Rrule" valign="top">18 (8%)</td><td align="left" styleCode="Botrule Rrule" valign="top">6 (2%)</td></tr></tbody></table> <table ID="t14" width="100%"><caption>Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients</caption><col width="16.623%" align="left"/><col width="20.844%" align="left"/><col width="20.844%" align="left"/><col width="20.844%" align="left"/><col width="20.844%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">1. Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">2. Patients without pre-transplant history of diabetes mellitus.</paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">3. 7-12 months for the U.S. trial.</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Status of PTDM</content><content styleCode="bold"><sup>1</sup></content></td><td colspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">US Trial</content></td><td colspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">European Trial</content></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus/MMF</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine/MMF</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus/AZA</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine/AZA</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Patients at risk <sup>2</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">75</td><td align="left" styleCode="Botrule Rrule" valign="top">83</td><td align="left" styleCode="Botrule Rrule" valign="top">132</td><td align="left" styleCode="Botrule Rrule" valign="top">138</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">New Onset PTDM <sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">10 (13%)</td><td align="left" styleCode="Botrule Rrule" valign="top">6 (7%)</td><td align="left" styleCode="Botrule Rrule" valign="top">29 (22%)</td><td align="left" styleCode="Botrule Rrule" valign="top">5 (4%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Patients still on insulin at 1 year <sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">7 (9%)</td><td align="left" styleCode="Botrule Rrule" valign="top">1 (1%)</td><td align="left" styleCode="Botrule Rrule" valign="top">24 (18%)</td><td align="left" styleCode="Botrule Rrule" valign="top">4 (3%)</td></tr></tbody></table>
7 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 ) 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 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. 2. High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate 3. CYP3A inhibitor.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 )] .
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 )] .
<table ID="t15" width="100%"><caption>Table 15: Effects of Other Drugs/Substances on Tacrolimus <sup>1</sup></caption><col width="33.333%" align="left"/><col width="33.333%" align="left"/><col width="33.333%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">1. Tacrolimus dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures <content styleCode="italics">[see Clinical Pharmacology ( <linkHtml href="#s77">12.3</linkHtml>)] </content>, literature reports of altered tacrolimus exposures, or the other drug's known CYP3A inhibitor/inducer status. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">2. High dose or double strength grapefruit juice is a <content styleCode="italics">strong</content>CYP3A inhibitor; low dose or single strength grapefruit juice is a <content styleCode="italics">moderate</content></paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">3. CYP3A inhibitor.Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting <content styleCode="italics">in vitro</content>CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate). </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Drug/Substance Class or Name</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Drug Interaction Effect</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Recommendations</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Grapefruit or grapefruit juice <sup>2</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s24">5.6</linkHtml>, <linkHtml href="#s29">5.11</linkHtml>, </content> <content styleCode="italics"><linkHtml href="#s30">5.12</linkHtml>)] </content>. </td><td align="left" styleCode="Botrule Rrule" valign="top">Avoid grapefruit or grapefruit juice.</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Strong CYP3A Inducers <sup>3</sup>: Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John's Wort </td><td align="left" styleCode="Botrule Rrule" valign="top">May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s29">5.11</linkHtml>)] </content>. </td><td align="left" styleCode="Botrule Rrule" valign="top">Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s9">2.2</linkHtml>, <linkHtml href="#s15">2.6</linkHtml>) and Clinical Pharmacology </content> <content styleCode="italics">( <linkHtml href="#s77">12.3</linkHtml>)] </content>.
s dose and monitor tacrolimus whole blood trough concentrations <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s9">2.2</linkHtml>, <linkHtml href="#s15">2.6</linkHtml>) and Clinical Pharmacology </content> <content styleCode="italics">( <linkHtml href="#s77">12.3</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Strong CYP3A Inhibitors <sup>3</sup>: Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, <content styleCode="italics">Schisandra sphenanthera</content>extracts </td><td align="left" styleCode="Botrule Rrule" valign="top">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 <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s24">5.6</linkHtml>, <linkHtml href="#s29">5.11</linkHtml>, </content> <content styleCode="italics"><linkHtml href="#s30">5.12</linkHtml>)] </content>. </td><td align="left" styleCode="Botrule Rrule" valign="top">Reduce tacrolimus dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s9">2.2</linkHtml>, <linkHtml href="#s15">2.6</linkHtml>) and </content> <content styleCode="italics">Clinical Pharmacology ( <linkHtml href="#s77">12.3</linkHtml>)] </content>. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary <content styleCode="italics">[see Warnings and</content> <content styleCode="italics">Precautions ( <linkHtml href="#s29">5.11</linkHtml>)]. </content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">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 </td><td align="left" styleCode="Botrule Rrule" valign="top">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s24">5.6</linkHtml>, <linkHtml href="#s29">5.11</linkHtml>, </content> <content styleCode="italics"><linkHtml href="#s30">5.12</linkHtml>)] </content>. </td><td align="left" styleCode="Botrule Rrule" valign="top">Monitor tacrolimus whole blood trough concentrations and reduce Tacrolimus dose if needed <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s9">2.2</linkHtml>, <linkHtml href="#s15">2.6</linkHtml>) and Clinical Pharmacology ( <linkHtml href="#s77">12.3</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide </td><td align="left" styleCode="Botrule Rrule" valign="top">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s24">5.6</linkHtml>, <linkHtml href="#s29">5.11</linkHtml>, </content> <content styleCode="italics"><linkHtml href="#s30">5.12</linkHtml>)] </content>.
and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s24">5.6</linkHtml>, <linkHtml href="#s29">5.11</linkHtml>, </content> <content styleCode="italics"><linkHtml href="#s30">5.12</linkHtml>)] </content>. </td><td align="left" styleCode="Botrule Rrule" valign="top">Monitor tacrolimus whole blood trough concentrations and reduce Tacrolimus dose if needed <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s9">2.2</linkHtml>, <linkHtml href="#s15">2.6</linkHtml>) and Clinical Pharmacology ( <linkHtml href="#s77">12.3</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone</td><td align="left" styleCode="Botrule Rrule" valign="top">May decrease tacrolimus whole blood trough concentrations.</td><td align="left" styleCode="Botrule Rrule" valign="top">Monitor tacrolimus whole blood trough concentrations and adjust Tacrolimus dose if needed <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s9">2.2</linkHtml>, <linkHtml href="#s15">2.6</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Caspofungin</td><td align="left" styleCode="Botrule Rrule" valign="top">May decrease tacrolimus whole blood trough concentrations.</td><td align="left" styleCode="Botrule Rrule" valign="top">Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s9">2.2</linkHtml>, <linkHtml href="#s15">2.6</linkHtml>)] </content>. </td></tr></tbody></table>
8 USE IN SPECIFIC POPULATIONS Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. ( 8.1 , 8.3 ) Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf ® (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to Tacrolimus 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data ]. The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death. Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population.
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 Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions ( 5.4 )]. Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions ( 5.7 , 5.8 )]. 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 Tacrolimus. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus. 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 16 . 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 renal 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 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus 1. Includes multiple births and terminations. 2. Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. Kidney Liver Pregnancy Outcomes 1 462 253 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% 2 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 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed.
kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), 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 to 6.9 times the recommended clinical dose range) 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 to 6.9 times the recommended clinical dose range); 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 to 2.2 times the recommended clinical dose range). 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 to 6.9 times the 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 to 2.2 times the recommended clinical dose range) [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 Use in Specific Populations ( 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 tacrolimus and any potential adverse effects on the breastfed child from tacrolimus or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Tacrolimus 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 Tacrolimus [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 tacrolimus [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use Safety and effectiveness have been established in pediatric liver transplant patients. Liver Transplantation Safety and efficacy in pediatric liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation.
pediatric liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 ). Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf ® (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 8.5 Geriatric Use Clinical trials of tacrolimus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 volunteers with normal renal function. However, consideration should be given to dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration ( 2.4 ) 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 volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology ( 12.3 )] . The use of Tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )]. 8.8 Race or Ethnicity African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]. 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 ( 5.4 )].
<table ID="t16" width="100%"><caption>Table 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus</caption><col width="33.333%" align="left"/><col width="33.333%" align="left"/><col width="33.333%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">1. Includes multiple births and terminations.</paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">2. Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Kidney</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Liver</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Pregnancy Outcomes</content><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">462</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">253</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Miscarriage</content></td><td align="left" styleCode="Botrule Rrule" valign="top">24.5%</td><td align="left" styleCode="Botrule Rrule" valign="top">25%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Live births</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">331</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">180</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Pre-term delivery (< 37 weeks)</td><td align="left" styleCode="Botrule Rrule" valign="top">49%</td><td align="left" styleCode="Botrule Rrule" valign="top">42%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Low birth weight (< 2500 g)</td><td align="left" styleCode="Botrule Rrule" valign="top">42%</td><td align="left" styleCode="Botrule Rrule" valign="top">30%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Birth defects</td><td align="left" styleCode="Botrule Rrule" valign="top">8% <content styleCode="italics"><sup>2</sup></content></td><td align="left" styleCode="Botrule Rrule" valign="top">5%</td></tr></tbody></table>
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to Tacrolimus 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data ]. The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death. Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long- term effects on the offspring were reported. Maternal Adverse Reactions Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions ( 5.4 )]. Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia.
g were reported. Maternal Adverse Reactions Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions ( 5.4 )]. Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions ( 5.7 , 5.8 )]. 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 Tacrolimus. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus. 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 16 . 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 renal 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 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus 1. Includes multiple births and terminations. 2. Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. Kidney Liver Pregnancy Outcomes 1 462 253 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% 2 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 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), 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 to 6.9 times the recommended clinical dose range) 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.
8.4 Pediatric Use Safety and effectiveness have been established in pediatric liver transplant patients. Liver Transplantation Safety and efficacy in pediatric liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 ). Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf ® (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
10 OVERDOSAGE Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of Tacrolimus [see Adverse Reactions ( 6.1 , 6.2 )] , including tremors, abnormal renal function, hypertension, and peripheral edema; in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
11 DESCRIPTION Tacrolimus, previously known as FK506, is the active ingredient in Tacrolimus. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis . Chemically, tacrolimus is designated as [3 S - [3 R *[ E (1 S *,3 S *,4 S *)], 4 S *,5 R *,8 S *,9 E ,12 R *,14 R *,15 S *,16 R *,18 S *,19 S *,26a R *]] - 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1- methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1- c ][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate. The chemical structure of tacrolimus is: Tacrolimus has an empirical formula of C 44 H 69 NO 12 •H 2 O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform. Tacrolimus injection is a sterile solution containing the equivalent of 5 mg anhydrous tacrolimus USP in 1 mL for administration by intravenous infusion only. Each mL contains the following inactive ingredients: dehydrated alcohol USP, 80.0% v/v and polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg. Tacrolimus injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use. Figure
12 CLINICAL PHARMACOLOGY 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, 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 1. Not applicable 2. AUC 0-inf 3. Not available 4. AUC 0-t 5. Determined after the first dose 6. Median [range] 7.AUC 0-12 Population N Route (Dose) Parameters C max (nanogram/mL) T max (hr) AUC (nanogram•hr/mL) t 1/2 (hr) CL (L/hr/kg) V (L/kg) Healthy Volunteers 8 Intravenous (0.025 mg/kg/4 hr) 1 1 652 2 ± 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 2 ± 95 32.3 ± 8.8 3 3 Kidney Transplant Patients 26 Intravenous (0.02 mg/kg/12 hr) 1 1 294 2 ± 262 18.8 ± 16.7 0.083 ± 0.050 1.41 ± 0.66 PO (0.2 mg/kg/day) 19.2 ± 10.3 3.0 203 2 ± 42 3 3 3 PO (0.3 mg/kg/day) 24.2 ± 15.8 1.5 288 2 ± 93 3 3 3 Liver Transplant Patients 17 Intravenous (0.05 mg/kg/12 hr) 1 1 3300 2 ±2130 11.7 ±3.9 0.053 ±0.017 0.85 ±0.30 PO (0.3 mg/kg/day) 68.5 ± 30.0 2.3 ± 1.5 519 2 ± 179 3 3 3 Heart Transplant Patients 11 Intravenous (0.01 mg/kg/day as a continuous infusion) 1 1 954 4 ± 334 23.6 ± 9.22 0.051 ± 0.015 3 11 PO (0.075 mg/kg/day) 5 14.7 ± 7.79 2.1 [0.5-6.0] 6 82.7 7 ± 63.2 1 3 3 14 PO (0.15 mg/kg/day) 5 24.5 ± 13.7 1.5 [0.4-4.0] 6 142 7 ± 116 1 3 3 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 Prograf® capsules.
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 Prograf® capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg Prograf® capsules. Tacrolimus maximum blood concentrations (C max ) 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 nanogram/mL measured at 10–12 hours post-dose (C min ) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 nanogram/mL, the correlation coefficient was 0.94. In 25 heart transplant patients over a concentration range of 2 to 24 nanogram/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 C max were decreased 37% and 77%, respectively; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max 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 C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C max was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. In 11 liver transplant patients, tacrolimus injection administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 ± 18%) and C max (50 ± 19%), as compared to a fasted state. Prograf® 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 5–50 nanogram/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 (CYP3A). 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.
oposed. 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 intravenous 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 intravenously-administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1.0% 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 Pediatric Patients Prograf® capsules Pharmacokinetics in Pediatric Patients Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following intravenous administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C max were 337 ± 167 nanogram∙hr/mL and 48.4 ± 27.9 nanogram/mL, respectively. The absolute bioavailability was 31 ± 24%. Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration ( 2.3 )]. Renal and Hepatic Impaired Patients The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19 . Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients 1. Corrected for bioavailability 2. 1 patient did not receive the PO dose Population (No. of Patients) Dose AUC 0-t (nanogram·hr/mL) t 1/2 (hr) V (L/kg) CI (L/hr/kg) Renal Impairment (n = 12) 0.02 mg/kg/4 hr IV 393 ± 123 (t = 60 hr) 26.3 ± 9.2 1.07 ± 0.20 0.038 ± 0.014 Mild Hepatic Impairment (n = 6) 0.02 mg/kg/4 hr IV 367 ± 107 (t = 72 hr) 60.6 ± 43.8 Range: 27.8 – 141 3.1 ± 1.6 0.042 ± 0.02 7.7 mg PO 488 ± 320 (t = 72 hr) 66.1 ± 44.8 Range: 29.5 – 138 3.7 ± 4.7 1 0.034 ± 0.019 1 Severe Hepatic Impairment (n = 6, IV) 0.02 mg/kg/4 hr Intravenous (n = 2) 0.01 mg/kg/8 hr Intravenous (n = 4) 762 ± 204 (t = 120 hr) 289 ± 117 (t = 144 hr) 198 ± 158 Range: 81 – 436 3.9 ± 1.0 0.017 ± 0.013 (n = 5, PO) 2 8 mg PO (n = 1) 5 mg PO (n = 4) 4 mg PO (n = 1) 658 (t = 120 hr) 533 ± 156 (t = 144 hr) 119 ± 35 Range: 85 – 178 3.1 ± 3.4 1 0.016 ± 0.011 1 Patients with Renal Impairment Tacrolimus pharmacokinetics, following a single intravenous administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant.
Range: 85 – 178 3.1 ± 3.4 1 0.016 ± 0.011 1 Patients with Renal Impairment Tacrolimus pharmacokinetics, following a single intravenous administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers ( Table 19 ) [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single intravenous and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.7 )] . Patients with Cystic Fibrosis Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration ( 2.2 , 2.3 )] . Racial or Ethnic Groups The pharmacokinetics of tacrolimus have been studied following single intravenous and oral administration of tacrolimus to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour intravenous infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (± SD) tacrolimus C max in African-Americans (23.6 ± 12.1 nanogram/mL) was significantly lower than in Caucasians (40.2 ± 12.6 nanogram/mL) and Latino-Americans (36.2 ± 15.8 nanogram/mL) (p < 0.01). Mean AUC 0 –inf tended to be lower in African-Americans (203 ± 115 nanogram∙hr/mL) than Caucasians (344 ± 186 nanogram∙hr/mL) and Latino-Americans (274 ± 150 nanogram∙hr/mL). The mean (± SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was significantly lower than in Caucasians (19 ± 5.8%, p = 0.011). There was no significant difference in mean terminal T 1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration ( 2.2 )] . Male and Female Patients A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences. 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 ) ] .
( 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 nanogram/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 and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus C max relative to tacrolimus administration alone [see Drug Interactions ( 7.2 ) ] . Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 ± 5% vs. 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 ± 0.129 L/hr/kg vs. 0.148 ± 0.043 L/hr/kg). Overall, intravenous clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions ( 7.2 ) ] . Voriconazole (see complete prescribing information for VFEND): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions ( 7.2 ) ] . Posaconazole (see complete prescribing information for Noxafil): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) C max and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions ( 7.2 ) ] . Caspofungin (see complete prescribing information for CANCIDAS): Caspofungin reduced the blood AUC 0–12 of tacrolimus by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions ( 7.2 ) ] . The mechanism of interaction has not been confirmed. Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf ® (tacrolimus) products.
th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions ( 7.2 ) ] . The mechanism of interaction has not been confirmed. Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf ® (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
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, 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 1. Not applicable 2. AUC 0-inf 3. Not available 4. AUC 0-t 5. Determined after the first dose 6. Median [range] 7.AUC 0-12 Population N Route (Dose) Parameters C max (nanogram/mL) T max (hr) AUC (nanogram•hr/mL) t 1/2 (hr) CL (L/hr/kg) V (L/kg) Healthy Volunteers 8 Intravenous (0.025 mg/kg/4 hr) 1 1 652 2 ± 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 2 ± 95 32.3 ± 8.8 3 3 Kidney Transplant Patients 26 Intravenous (0.02 mg/kg/12 hr) 1 1 294 2 ± 262 18.8 ± 16.7 0.083 ± 0.050 1.41 ± 0.66 PO (0.2 mg/kg/day) 19.2 ± 10.3 3.0 203 2 ± 42 3 3 3 PO (0.3 mg/kg/day) 24.2 ± 15.8 1.5 288 2 ± 93 3 3 3 Liver Transplant Patients 17 Intravenous (0.05 mg/kg/12 hr) 1 1 3300 2 ±2130 11.7 ±3.9 0.053 ±0.017 0.85 ±0.30 PO (0.3 mg/kg/day) 68.5 ± 30.0 2.3 ± 1.5 519 2 ± 179 3 3 3 Heart Transplant Patients 11 Intravenous (0.01 mg/kg/day as a continuous infusion) 1 1 954 4 ± 334 23.6 ± 9.22 0.051 ± 0.015 3 11 PO (0.075 mg/kg/day) 5 14.7 ± 7.79 2.1 [0.5-6.0] 6 82.7 7 ± 63.2 1 3 3 14 PO (0.15 mg/kg/day) 5 24.5 ± 13.7 1.5 [0.4-4.0] 6 142 7 ± 116 1 3 3 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 Prograf® capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg Prograf® capsules. Tacrolimus maximum blood concentrations (C max ) 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 nanogram/mL measured at 10–12 hours post-dose (C min ) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 nanogram/mL, the correlation coefficient was 0.94. In 25 heart transplant patients over a concentration range of 2 to 24 nanogram/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.
ange of 2 to 24 nanogram/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 C max were decreased 37% and 77%, respectively; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max 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 C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C max was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. In 11 liver transplant patients, tacrolimus injection administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 ± 18%) and C max (50 ± 19%), as compared to a fasted state. Prograf® 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 5–50 nanogram/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 (CYP3A). 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 intravenous 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 intravenously-administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1.0% 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%.
nation 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 Pediatric Patients Prograf® capsules Pharmacokinetics in Pediatric Patients Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following intravenous administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C max were 337 ± 167 nanogram∙hr/mL and 48.4 ± 27.9 nanogram/mL, respectively. The absolute bioavailability was 31 ± 24%. Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration ( 2.3 )]. Renal and Hepatic Impaired Patients The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19 . Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients 1. Corrected for bioavailability 2. 1 patient did not receive the PO dose Population (No. of Patients) Dose AUC 0-t (nanogram·hr/mL) t 1/2 (hr) V (L/kg) CI (L/hr/kg) Renal Impairment (n = 12) 0.02 mg/kg/4 hr IV 393 ± 123 (t = 60 hr) 26.3 ± 9.2 1.07 ± 0.20 0.038 ± 0.014 Mild Hepatic Impairment (n = 6) 0.02 mg/kg/4 hr IV 367 ± 107 (t = 72 hr) 60.6 ± 43.8 Range: 27.8 – 141 3.1 ± 1.6 0.042 ± 0.02 7.7 mg PO 488 ± 320 (t = 72 hr) 66.1 ± 44.8 Range: 29.5 – 138 3.7 ± 4.7 1 0.034 ± 0.019 1 Severe Hepatic Impairment (n = 6, IV) 0.02 mg/kg/4 hr Intravenous (n = 2) 0.01 mg/kg/8 hr Intravenous (n = 4) 762 ± 204 (t = 120 hr) 289 ± 117 (t = 144 hr) 198 ± 158 Range: 81 – 436 3.9 ± 1.0 0.017 ± 0.013 (n = 5, PO) 2 8 mg PO (n = 1) 5 mg PO (n = 4) 4 mg PO (n = 1) 658 (t = 120 hr) 533 ± 156 (t = 144 hr) 119 ± 35 Range: 85 – 178 3.1 ± 3.4 1 0.016 ± 0.011 1 Patients with Renal Impairment Tacrolimus pharmacokinetics, following a single intravenous administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers ( Table 19 ) [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single intravenous and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10).
ing single intravenous and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.7 )] . Patients with Cystic Fibrosis Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration ( 2.2 , 2.3 )] . Racial or Ethnic Groups The pharmacokinetics of tacrolimus have been studied following single intravenous and oral administration of tacrolimus to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour intravenous infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (± SD) tacrolimus C max in African-Americans (23.6 ± 12.1 nanogram/mL) was significantly lower than in Caucasians (40.2 ± 12.6 nanogram/mL) and Latino-Americans (36.2 ± 15.8 nanogram/mL) (p < 0.01). Mean AUC 0 –inf tended to be lower in African-Americans (203 ± 115 nanogram∙hr/mL) than Caucasians (344 ± 186 nanogram∙hr/mL) and Latino-Americans (274 ± 150 nanogram∙hr/mL). The mean (± SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was significantly lower than in Caucasians (19 ± 5.8%, p = 0.011). There was no significant difference in mean terminal T 1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration ( 2.2 )] . Male and Female Patients A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences. 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 nanogram/mL. It is recommended to avoid concomitant use of tacrolimus and nelfinavir unless the benefits outweigh the risks [see Drug Interactions ( 7.2 ) ] .
ificantly 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 nanogram/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 and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus C max relative to tacrolimus administration alone [see Drug Interactions ( 7.2 ) ] . Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 ± 5% vs. 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 ± 0.129 L/hr/kg vs. 0.148 ± 0.043 L/hr/kg). Overall, intravenous clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions ( 7.2 ) ] . Voriconazole (see complete prescribing information for VFEND): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions ( 7.2 ) ] . Posaconazole (see complete prescribing information for Noxafil): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) C max and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions ( 7.2 ) ] . Caspofungin (see complete prescribing information for CANCIDAS): Caspofungin reduced the blood AUC 0–12 of tacrolimus by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions ( 7.2 ) ] . The mechanism of interaction has not been confirmed. Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf ® (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
<table ID="t17" width="100%"><caption>Table 17. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients</caption><col width="11.720%" align="left"/><col width="5.043%" align="left"/><col width="13.453%" align="left"/><col width="11.631%" align="left"/><col width="11.631%" align="left"/><col width="11.631%" align="left"/><col width="11.631%" align="left"/><col width="11.631%" align="left"/><col width="11.631%" align="left"/><tfoot><tr><td colspan="9" align="left" valign="top"><paragraph styleCode="footnote">1. Not applicable</paragraph></td></tr><tr><td colspan="9" align="left" valign="top"><paragraph styleCode="footnote">2. AUC <sub>0-inf</sub></paragraph></td></tr><tr><td colspan="9" align="left" valign="top"><paragraph styleCode="footnote">3. Not available</paragraph></td></tr><tr><td colspan="9" align="left" valign="top"><paragraph styleCode="footnote">4. AUC <sub>0-t</sub></paragraph></td></tr><tr><td colspan="9" align="left" valign="top"><paragraph styleCode="footnote">5. Determined after the first dose</paragraph></td></tr><tr><td colspan="9" align="left" valign="top"><paragraph styleCode="footnote">6.
="9" align="left" valign="top"><paragraph styleCode="footnote">4. AUC <sub>0-t</sub></paragraph></td></tr><tr><td colspan="9" align="left" valign="top"><paragraph styleCode="footnote">5. Determined after the first dose</paragraph></td></tr><tr><td colspan="9" align="left" valign="top"><paragraph styleCode="footnote">6. Median [range]</paragraph></td></tr><tr><td colspan="9" align="left" valign="top"><paragraph styleCode="footnote">7.AUC <sub>0-12</sub></paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Population</content></td><td rowspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">N</content> </td><td rowspan="2" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Route (Dose)</content></td><td colspan="6" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Parameters</content></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">C <sub>max</sub>(nanogram/mL) </td><td align="left" styleCode="Botrule Rrule" valign="top">T <sub>max</sub>(hr) </td><td align="left" styleCode="Botrule Rrule" valign="top">AUC (nanogram•hr/mL)</td><td align="left" styleCode="Botrule Rrule" valign="top">t <sub>1/2</sub>(hr) </td><td align="left" styleCode="Botrule Rrule" valign="top">CL (L/hr/kg)</td><td align="left" styleCode="Botrule Rrule" valign="top">V (L/kg)</td></tr><tr><td rowspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top">Healthy Volunteers</td><td align="left" styleCode="Botrule Rrule" valign="top">8</td><td align="left" styleCode="Botrule Rrule" valign="top">Intravenous (0.025 mg/kg/4 hr)</td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">652 <sup>2</sup>± 156 </td><td align="left" styleCode="Botrule Rrule" valign="top">34.2 ± 7.7</td><td align="left" styleCode="Botrule Rrule" valign="top">0.040 ± 0.009</td><td align="left" styleCode="Botrule Rrule" valign="top">1.91 ± 0.31</td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">16</td><td align="left" styleCode="Botrule Rrule" valign="top">PO (5 mg) (capsules)</td><td align="left" styleCode="Botrule Rrule" valign="top">28.8 ± 8.9</td><td align="left" styleCode="Botrule Rrule" valign="top">1.5 ± 0.7</td><td align="left" styleCode="Botrule Rrule" valign="top">266 <sup>2</sup>± 95 </td><td align="left" styleCode="Botrule Rrule" valign="top">32.3 ± 8.8</td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td></tr><tr><td rowspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top">Kidney Transplant Patients</td><td rowspan="3" align="left" styleCode="Botrule Rrule" valign="top">26</td><td align="left" styleCode="Botrule Rrule" valign="top">Intravenous (0.02 mg/kg/12 hr)</td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">294 <sup>2</sup>± 262 </td><td align="left" styleCode="Botrule Rrule" valign="top">18.8 ± 16.7</td><td align="left" styleCode="Botrule Rrule" valign="top">0.083 ± 0.050</td><td align="left" styleCode="Botrule Rrule" valign="top">1.41 ± 0.66</td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">PO (0.2 mg/kg/day)</td><td align="left" styleCode="Botrule Rrule" valign="top">19.2 ± 10.3</td><td align="left" styleCode="Botrule Rrule" valign="top">3.0</td><td alig
0</td><td align="left" styleCode="Botrule Rrule" valign="top">1.41 ± 0.66</td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">PO (0.2 mg/kg/day)</td><td align="left" styleCode="Botrule Rrule" valign="top">19.2 ± 10.3</td><td align="left" styleCode="Botrule Rrule" valign="top">3.0</td><td alig n="left" styleCode="Botrule Rrule" valign="top">203 <sup>2</sup>± 42 </td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">PO (0.3 mg/kg/day)</td><td align="left" styleCode="Botrule Rrule" valign="top">24.2 ± 15.8</td><td align="left" styleCode="Botrule Rrule" valign="top">1.5</td><td align="left" styleCode="Botrule Rrule" valign="top">288 <sup>2</sup>± 93 </td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td></tr><tr><td rowspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top">Liver Transplant Patients</td><td rowspan="2" align="left" styleCode="Botrule Rrule" valign="top">17</td><td align="left" styleCode="Botrule Rrule" valign="top">Intravenous (0.05 mg/kg/12 hr)</td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">3300 <sup>2</sup>±2130 </td><td align="left" styleCode="Botrule Rrule" valign="top">11.7 ±3.9</td><td align="left" styleCode="Botrule Rrule" valign="top">0.053 ±0.017</td><td align="left" styleCode="Botrule Rrule" valign="top">0.85 ±0.30</td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">PO (0.3 mg/kg/day)</td><td align="left" styleCode="Botrule Rrule" valign="top">68.5 ± 30.0</td><td align="left" styleCode="Botrule Rrule" valign="top">2.3 ± 1.5</td><td align="left" styleCode="Botrule Rrule" valign="top">519 <sup>2</sup>± 179 </td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td></tr><tr><td rowspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"> Heart Transplant Patients </td><td align="left" styleCode="Botrule Rrule" valign="top">11</td><td align="left" styleCode="Botrule Rrule" valign="top">Intravenous (0.01 mg/kg/day as a continuous infusion)</td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">954 <sup>4</sup>± 334 </td><td align="left" styleCode="Botrule Rrule" valign="top">23.6 ± 9.22</td><td align="left" styleCode="Botrule Rrule" valign="top">0.051 ± 0.015</td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">11</td><td align="left" styleCode="Botrule Rrule" valign="top">PO (0.075 mg/kg/day) <sup>5</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">14.7 ± 7.79</td><td align="left" styleCode="Botrule Rrule" valign="top">2.1 [0.5-6.0] <sup>6</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">82.7 <sup>7</sup>± 63.2 </td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">
[0.5-6.0] <sup>6</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">82.7 <sup>7</sup>± 63.2 </td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"> <sup>3</sup></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">14</td><td align="left" styleCode="Botrule Rrule" valign="top">PO (0.15 mg/kg/day) <sup>5</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">24.5 ± 13.7</td><td align="left" styleCode="Botrule Rrule" valign="top">1.5 [0.4-4.0] <sup>6</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">142 <sup>7</sup>± 116 </td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td><td align="left" styleCode="Botrule Rrule" valign="top"><sup>3</sup></td></tr></tbody></table> <table ID="t19" width="100%"><caption>Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients</caption><col width="16.667%" align="left"/><col width="16.667%" align="left"/><col width="16.667%" align="left"/><col width="16.667%" align="left"/><col width="16.667%" align="left"/><col width="16.667%" align="left"/><tfoot><tr><td colspan="6" align="left" valign="top"><paragraph styleCode="footnote">1. Corrected for bioavailability</paragraph></td></tr><tr><td colspan="6" align="left" valign="top"><paragraph styleCode="footnote">2. 1 patient did not receive the PO dose</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top">Population (No.
styleCode="footnote">1. Corrected for bioavailability</paragraph></td></tr><tr><td colspan="6" align="left" valign="top"><paragraph styleCode="footnote">2. 1 patient did not receive the PO dose</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top">Population (No. of Patients) </td><td align="left" styleCode="Toprule Botrule Rrule" valign="top">Dose</td><td align="left" styleCode="Toprule Botrule Rrule" valign="top">AUC <sub>0-t</sub>(nanogram·hr/mL) </td><td align="left" styleCode="Toprule Botrule Rrule" valign="top">t <sub>1/2</sub>(hr) </td><td align="left" styleCode="Toprule Botrule Rrule" valign="top">V (L/kg)</td><td align="left" styleCode="Toprule Botrule Rrule" valign="top">CI (L/hr/kg)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Renal Impairment (n = 12) </td><td align="left" styleCode="Botrule Rrule" valign="top">0.02 mg/kg/4 hr IV </td><td align="left" styleCode="Botrule Rrule" valign="top">393 ± 123 (t = 60 hr) </td><td align="left" styleCode="Botrule Rrule" valign="top">26.3 ± 9.2</td><td align="left" styleCode="Botrule Rrule" valign="top">1.07 ± 0.20</td><td align="left" styleCode="Botrule Rrule" valign="top">0.038 ± 0.014</td></tr><tr><td rowspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top">Mild Hepatic Impairment (n = 6) </td><td align="left" styleCode="Botrule Rrule" valign="top">0.02 mg/kg/4 hr IV </td><td align="left" styleCode="Botrule Rrule" valign="top">367 ± 107 (t = 72 hr) </td><td align="left" styleCode="Botrule Rrule" valign="top">60.6 ± 43.8 Range: 27.8 – 141 </td><td align="left" styleCode="Botrule Rrule" valign="top">3.1 ± 1.6</td><td align="left" styleCode="Botrule Rrule" valign="top">0.042 ± 0.02</td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">7.7 mg PO</td><td align="left" styleCode="Botrule Rrule" valign="top">488 ± 320 (t = 72 hr) </td><td align="left" styleCode="Botrule Rrule" valign="top">66.1 ± 44.8 Range: 29.5 – 138 </td><td align="left" styleCode="Botrule Rrule" valign="top">3.7 ± 4.7 <sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">0.034 ± 0.019 <sup>1</sup></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Severe Hepatic Impairment (n = 6, IV) </td><td align="left" styleCode="Botrule Rrule" valign="top">0.02 mg/kg/4 hr Intravenous (n = 2) 0.01 mg/kg/8 hr Intravenous (n = 4) </td><td align="left" styleCode="Botrule Rrule" valign="top">762 ± 204 (t = 120 hr) 289 ± 117 (t = 144 hr) </td><td align="left" styleCode="Botrule Rrule" valign="top">198 ± 158 Range: 81 – 436 </td><td align="left" styleCode="Botrule Rrule" valign="top">3.9 ± 1.0</td><td align="left" styleCode="Botrule Rrule" valign="top">0.017 ± 0.013</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">(n = 5, PO) <sup>2</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">8 mg PO (n = 1) 5 mg PO (n = 4) 4 mg PO (n = 1) </td><td align="left" styleCode="Botrule Rrule" valign="top">658 (t = 120 hr) 533 ± 156 (t = 144 hr) </td><td align="left" styleCode="Botrule Rrule" valign="top">119 ± 35 Range: 85 – 178 </td><td align="left" styleCode="Botrule Rrule" valign="top">3.1 ± 3.4 <sup>1</sup></td><td align="left" styleCode="Botrule Rrule" valign="top">0.016 ± 0.011 <sup>1</sup></td></tr></tbody></table>
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions ( 5.1 )] . A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% – 3%), equivalent to tacrolimus doses of 1.1–118 mg/kg/day or 3.3–354 mg/m 2 /day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown. The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system's ability to inhibit unrelated carcinogenesis. Mutagenesis No evidence of genotoxicity was seen in bacterial ( Salmonella and E. coli ) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Impairment of Fertility Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m 2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post- implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions ( 5.1 )] . A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% – 3%), equivalent to tacrolimus doses of 1.1–118 mg/kg/day or 3.3–354 mg/m 2 /day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown. The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system's ability to inhibit unrelated carcinogenesis. Mutagenesis No evidence of genotoxicity was seen in bacterial ( Salmonella and E. coli ) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Impairment of Fertility Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m 2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post- implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
14 CLINICAL STUDIES 14.1 Kidney Transplantation Tacrolimus /Azathioprine (AZA) Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded. There were 205 patients randomized to tacrolimus-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids, and azathioprine. Overall, 1-year patient and graft survivals were 96.1% and 89.6%, respectively. Data from this trial of tacrolimus in conjunction with azathioprine indicate that during the first 3 months of that trial, 80% of the patients maintained trough concentrations between 7-20 nanogram/mL, and then between 5-15 nanogram/mL, through 1 year. Tacrolimus/Mycophenolate Mofetil (MMF) Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multicenter trial (Study 1), 1589 kidney transplant patients received Tacrolimus (Group C, n = 401), sirolimus (Group D, n = 399), or one of two cyclosporine (CsA) regimens (Group A, n = 390 and Group B, n = 399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving Tacrolimus/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the Tacrolimus group exhibited higher estimated creatinine clearance rates (eCL cr ) using the Cockcroft-Gault formula ( Table 20 ) and experienced fewer efficacy failures, defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or loss to follow-up ( Table 21 ) in comparison to each of the other three groups. Patients randomized to Tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions ( 6.1 )]. Table 20. Estimated Creatinine Clearance at 12 Months (Study 1) 1. All death/graft loss (n = 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n = 10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. 2. Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
nine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. 2. Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. eCL cr [mL/min] at Month 12 1 N MEAN SD MEDIAN Treatment Difference with Group C (99.2% CI 2 ) (A) CsA/MMF/CS 390 56.5 25.8 56.9 -8.6 (-13.7, -3.7) (B) CsA/MMF/CS/Daclizumab 399 58.9 25.6 60.9 -6.2 (-11.2, -1.2) (C) Tac/MMF/CS/Daclizumab 401 65.1 27.4 66.2 - (D) Siro/MMF/CS/Daclizumab 399 56.2 27.4 57.3 -8.9 (-14.1, -3.9) Total 1589 59.2 26.8 60.5 Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus Table 21. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1) 1. Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. Group A N = 390 Group B N = 399 Group C N = 401 Group D N = 399 Overall Failure 141 (36.2%) 126 (31.6%) 82 (20.4%) 185 (46.4%) Components of efficacy failure BPAR 113 (29.0%) 106 (26.6%) 60 (15.0%) 152 (38.1%) Graft loss excluding death 28 (7.2%) 20 (5.0%) 12 (3.0%) 30 (7.5%) Mortality 13 (3.3%) 7 (1.8%) 11 (2.7%) 12 (3.0%) Lost to follow-up 5 (1.3%) 7 (1.8%) 5 (1.3%) 6 (1.5%) Treatment Difference of efficacy failure compared to Group C (99.2% CI 1 ) 15.8% (7.1%, 24.3%) 11.2% (2.7%, 19.5%) - 26.0% (17.2%, 34.7%) Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab The protocol-specified target tacrolimus trough concentrations (C trough , Tac ) were 3-7 nanogram/mL; however, the observed median C troughs , Tac approximated 7 nanogram/mL throughout the 12-month trial ( Table 22 ). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 nanogram/mL through 1 year post-transplant. Table 22. Tacrolimus Whole Blood Trough Concentration Range (Study 1) 1. 10 to 90 th Percentile: range of C trough,Tac that excludes lowest 10% and highest 10% of C trough,Tac Time Median (P10-P90 1 ) tacrolimus whole blood trough concentration range (nanogram/mL) Day 30 (N = 366) 6.9 (4.4 – 11.3) Day 90 (N = 351) 6.8 (4.1 – 10.7) Day 180 (N = 355) 6.5 (4.0 – 9.6) Day 365 (N = 346) 6.5 (3.8 – 10.0) The protocol-specified target cyclosporine trough concentrations (C trough , CsA ) for Group B were 50-100 nanogram/mL; however, the observed median C troughs , CsA approximated 100 nanogram/mL throughout the 12-month trial. The protocol-specified target C troughs , CsA for Group A were 150-300 nanogram/mL for the first 3 months and 100-200 nanogram/mL from month 4 to month 12; the observed median C troughs , CsA approximated 225 nanogram/mL for the first 3 months and 140 nanogram/mL from month 4 to month 12. While patients in all groups started MMF at 1 gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 ( Table 23 ); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions. Table 23. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1) 1. Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time- averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.
rse reactions. Table 23. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1) 1. Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time- averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. Time period (Days) Time-averaged MMF dose (grams per day) 1 Less than 2.0 2.0 Greater than 2.0 0-30 (N = 364) 37% 60% 2% 0-90 (N = 373) 47% 51% 2% 0-180 (N = 377) 56% 42% 2% 0-365 (N = 380) 63% 36% 1% Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) In a second randomized, open-label, multicenter trial (Study 2), 424 kidney transplant patients received Tacrolimus (N = 212) or cyclosporine (N = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the Tacrolimus/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving Tacrolimus/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to over-immunosuppression ( Table 24 ). Table 24. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2) 1. 95% confidence interval calculated using Fisher's Exact Test. Tacrolimus/MMF (N = 212) Cyclosporine/MMF (N = 212) Overall Failure 32 (15.1%) 36 (17.0%) Components of efficacy failure BPAR 16 (7.5%) 29 (13.7%) Graft loss excluding death 6 (2.8%) 4 (1.9%) Mortality 9 (4.2%) 5 (2.4%) Lost to follow-up 4 (1.9%) 1 (0.5%) Treatment Difference of efficacy failure compared to Tacrolimus/MMF group (95% CI 1 ) 1.9% (-5.2%, 9.0%) The protocol-specified target tacrolimus whole blood trough concentrations (C trough , Tac ) in Study 2 were 7-16 nanogram/mL for the first three months and 5-15 nanogram/mL thereafter. The observed median C troughs , Tac approximated 10 nanogram/mL during the first three months and 8 nanogram/mL from month 4 to month 12 ( Table 25 ). Approximately 80% of patients maintained tacrolimus whole blood trough concentrations between 6 to 16 nanogram/mL during months 1 through 3 and, then, between 5 to 12 nanogram/mL from month 4 through 1 year. Table 25. Tacrolimus Whole Blood Trough Concentration Range (Study 2) 1. 10 to 90 th Percentile: range of C trough,Tac that excludes lowest 10% and highest 10% of C trough,Tac . Time Median (P10-P90 1 ) tacrolimus whole blood trough concentration range (nanogram/mL) Day 30 (N = 174) 10.5 (6.3 – 16.8) Day 60 (N = 179) 9.2 (5.9 – 15.3) Day 120 (N = 176) 8.3 (4.6 – 13.3) Day 180 (N = 171) 7.8 (5.5 – 13.2) Day 365 (N = 178) 7.1 (4.2 – 12.4) The protocol-specified target cyclosporine whole blood concentrations (C trough , CsA ) were 125 to 400 nanogram/mL for the first three months, and 100 to 300 nanogram/mL thereafter. The observed median C troughs , CsA approximated 280 nanogram/mL during the first three months and 190 nanogram/mL from month 4 to month 12. Patients in both groups started MMF at 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the tacrolimus/MMF group ( Table 26 ) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the tacrolimus/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions ( 6.1 )] . Table 26. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2) 1. Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods.
se Reactions ( 6.1 )] . Table 26. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2) 1. Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods. Time period (Days) Time-averaged MMF dose (g/day) 1 Less than 2.0 2.0 Greater than 2.0 0-30 (N = 212) 25% 69% 6% 0-90 (N = 212) 41% 53% 6% 0-180 (N = 212) 52% 41% 7% 0-365 (N = 212) 62% 34% 4% Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment) 14.2 Liver Transplantation The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation. In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed. In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases. One-year patient survival and graft survival in the Tacrolimus-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and tacrolimus-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and tacrolimus-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from intravenous to oral tacrolimus dosing was 2 days. Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 nanogram/mL. Long-term post-transplant patients are often maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL. 14.3 Heart Transplantation Two open-label, randomized, comparative trials evaluated the safety and efficacy of tacrolimus-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with tacrolimus or cyclosporine modified for 18 months.
he safety and efficacy of tacrolimus-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with tacrolimus or cyclosporine modified for 18 months. In a 3-arm trial conducted in the U.S., 331 patients received corticosteroids and tacrolimus plus sirolimus, tacrolimus plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year. In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the tacrolimus plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 nanogram/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 nanogram/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from 1 week to 3 months post-transplant, approximately 80% of patients maintained trough concentrations between 8 to 20 nanogram/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to 18 nanogram/mL. The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose tacrolimus; however, this regimen was associated with increased risk of wound-healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions ( 5.10 )].
<table ID="t20" width="100%"><caption>Table 20. Estimated Creatinine Clearance at 12 Months (Study 1)</caption><col width="28.417%" align="left"/><col width="13.800%" align="left"/><col width="13.800%" align="left"/><col width="13.800%" align="left"/><col width="13.800%" align="left"/><col width="16.383%" align="left"/><tfoot><tr><td colspan="6" align="left" valign="top"><paragraph styleCode="footnote">1. All death/graft loss (n = 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n = 10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing.</paragraph></td></tr><tr><td colspan="6" align="left" valign="top"><paragraph styleCode="footnote">2.
3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing.</paragraph></td></tr><tr><td colspan="6" align="left" valign="top"><paragraph styleCode="footnote">2. Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td colspan="5" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">eCL</content><content styleCode="bold"><sub>cr</sub></content><content styleCode="bold">[mL/min] at Month 12</content><sup>1</sup></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"/><td align="left" styleCode="Botrule Rrule" valign="top"> <content styleCode="bold">N</content></td><td align="left" styleCode="Botrule Rrule" valign="top"> <content styleCode="bold">MEAN</content></td><td align="left" styleCode="Botrule Rrule" valign="top"> <content styleCode="bold">SD</content></td><td align="left" styleCode="Botrule Rrule" valign="top"> <content styleCode="bold">MEDIAN</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Treatment Difference with Group C (99.2% CI</content><sup>2</sup><content styleCode="bold">)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">(A) CsA/MMF/CS</td><td align="left" styleCode="Botrule Rrule" valign="top">390</td><td align="left" styleCode="Botrule Rrule" valign="top">56.5</td><td align="left" styleCode="Botrule Rrule" valign="top">25.8</td><td align="left" styleCode="Botrule Rrule" valign="top">56.9</td><td align="left" styleCode="Botrule Rrule" valign="top">-8.6 (-13.7, -3.7)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">(B) CsA/MMF/CS/Daclizumab</td><td align="left" styleCode="Botrule Rrule" valign="top">399</td><td align="left" styleCode="Botrule Rrule" valign="top">58.9</td><td align="left" styleCode="Botrule Rrule" valign="top">25.6</td><td align="left" styleCode="Botrule Rrule" valign="top">60.9</td><td align="left" styleCode="Botrule Rrule" valign="top">-6.2 (-11.2, -1.2)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">(C) Tac/MMF/CS/Daclizumab</td><td align="left" styleCode="Botrule Rrule" valign="top">401</td><td align="left" styleCode="Botrule Rrule" valign="top">65.1</td><td align="left" styleCode="Botrule Rrule" valign="top">27.4</td><td align="left" styleCode="Botrule Rrule" valign="top">66.2</td><td align="left" styleCode="Botrule Rrule" valign="top">-</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">(D) Siro/MMF/CS/Daclizumab</td><td align="left" styleCode="Botrule Rrule" valign="top">399</td><td align="left" styleCode="Botrule Rrule" valign="top">56.2</td><td align="left" styleCode="Botrule Rrule" valign="top">27.4</td><td align="left" styleCode="Botrule Rrule" valign="top">57.3</td><td align="left" styleCode="Botrule Rrule" valign="top">-8.9 (-14.1, -3.9)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Total</td><td align="left" styleCode="Botrule Rrule" valign="top">1589</td><td align="left" styleCode="Botrule Rrule" valign="top">59.2</td><td align="left" styleCode="Botrule Rrule" valign="top">26.8</td><td align="left" styleCode="Botrule Rrule" valign="top">60.5</td><td align="left" styleCode="Botrule Rrule" valign="top"/></tr><tr><td colspan="6" align="left" styleCode="Botrule Lrule Rrule" valign="top">Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus</td></tr></tbody></table>
6.8</td><td align="left" styleCode="Botrule Rrule" valign="top">60.5</td><td align="left" styleCode="Botrule Rrule" valign="top"/></tr><tr><td colspan="6" align="left" styleCode="Botrule Lrule Rrule" valign="top">Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus</td></tr></tbody></table> <table ID="t21" width="100%"><caption>Table 21. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1)</caption><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">1.
ath, or Loss to Follow-up at 12 Months (Study 1)</caption><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">1. Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Group A N = 390</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Group B N = 399</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Group C N = 401</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Group D N = 399</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Overall Failure</td><td align="left" styleCode="Botrule Rrule" valign="top">141 (36.2%)</td><td align="left" styleCode="Botrule Rrule" valign="top">126 (31.6%)</td><td align="left" styleCode="Botrule Rrule" valign="top">82 (20.4%)</td><td align="left" styleCode="Botrule Rrule" valign="top">185 (46.4%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Components of efficacy failure</td><td align="left" styleCode="Botrule Rrule" valign="top"/><td align="left" styleCode="Botrule Rrule" valign="top"/><td align="left" styleCode="Botrule Rrule" valign="top"/><td align="left" styleCode="Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> BPAR</td><td align="left" styleCode="Botrule Rrule" valign="top">113 (29.0%)</td><td align="left" styleCode="Botrule Rrule" valign="top">106 (26.6%)</td><td align="left" styleCode="Botrule Rrule" valign="top">60 (15.0%)</td><td align="left" styleCode="Botrule Rrule" valign="top">152 (38.1%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Graft loss excluding death</td><td align="left" styleCode="Botrule Rrule" valign="top">28 (7.2%)</td><td align="left" styleCode="Botrule Rrule" valign="top">20 (5.0%)</td><td align="left" styleCode="Botrule Rrule" valign="top">12 (3.0%)</td><td align="left" styleCode="Botrule Rrule" valign="top">30 (7.5%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Mortality</td><td align="left" styleCode="Botrule Rrule" valign="top">13 (3.3%)</td><td align="left" styleCode="Botrule Rrule" valign="top">7 (1.8%)</td><td align="left" styleCode="Botrule Rrule" valign="top">11 (2.7%)</td><td align="left" styleCode="Botrule Rrule" valign="top">12 (3.0%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Lost to follow-up</td><td align="left" styleCode="Botrule Rrule" valign="top">5 (1.3%)</td><td align="left" styleCode="Botrule Rrule" valign="top">7 (1.8%)</td><td align="left" styleCode="Botrule Rrule" valign="top">5 (1.3%)</td><td align="left" styleCode="Botrule Rrule" valign="top">6 (1.5%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Treatment Difference of efficacy failure compared to Group C (99.2% CI <sup>1</sup>) </td><td align="left" styleCode="Botrule Rrule" valign="top">15.8% (7.1%, 24.3%) </td><td align="left" styleCode="Botrule Rrule" valign="top">11.2% (2.7%, 19.5%) </td><td align="left" styleCode="Botrule Rrule" valign="top"> - </td><td align="left" styleCode="Botrule Rrule" valign="top">26.0% (17.2%, 34.7%) </td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top">Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, a
5%) </td><td align="left" styleCode="Botrule Rrule" valign="top"> - </td><td align="left" styleCode="Botrule Rrule" valign="top">26.0% (17.2%, 34.7%) </td></tr><tr><td colspan="5" align="left" styleCode="Botrule Lrule Rrule" valign="top">Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, a nd D = Siro/MMF/CS/Daclizumab</td></tr></tbody></table> <table ID="t22" width="100%"><caption>Table 22. Tacrolimus Whole Blood Trough Concentration Range (Study 1)</caption><col width="20.650%" align="left"/><col width="79.350%" align="left"/><tfoot><tr><td colspan="2" align="left" valign="top"><paragraph styleCode="footnote">1. 10 to 90 <sup>th</sup>Percentile: range of C <sub>trough,Tac</sub>that excludes lowest 10% and highest 10% of C <sub>trough,Tac</sub></paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Time</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Median (P10-P90</content><sup>1</sup><content styleCode="bold">) tacrolimus whole blood trough concentration range (nanogram/mL)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 30 (N = 366)</td><td align="left" styleCode="Botrule Rrule" valign="top">6.9 (4.4 – 11.3)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 90 (N = 351)</td><td align="left" styleCode="Botrule Rrule" valign="top">6.8 (4.1 – 10.7)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 180 (N = 355)</td><td align="left" styleCode="Botrule Rrule" valign="top">6.5 (4.0 – 9.6)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 365 (N = 346)</td><td align="left" styleCode="Botrule Rrule" valign="top">6.5 (3.8 – 10.0)</td></tr></tbody></table>
le" valign="top">Day 180 (N = 355)</td><td align="left" styleCode="Botrule Rrule" valign="top">6.5 (4.0 – 9.6)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 365 (N = 346)</td><td align="left" styleCode="Botrule Rrule" valign="top">6.5 (3.8 – 10.0)</td></tr></tbody></table> <table ID="t23" width="100%"><caption>Table 23. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)</caption><col width="16.921%" align="left"/><col width="27.693%" align="left"/><col width="27.693%" align="left"/><col width="27.693%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">1. Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time- averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Time period (Days)</content></td><td colspan="3" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Time-averaged MMF dose (grams per day)</content><sup>1</sup></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">Less than 2.0</td><td align="left" styleCode="Botrule Rrule" valign="top">2.0</td><td align="left" styleCode="Botrule Rrule" valign="top">Greater than 2.0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0-30 (N = 364)</td><td align="left" styleCode="Botrule Rrule" valign="top">37%</td><td align="left" styleCode="Botrule Rrule" valign="top">60%</td><td align="left" styleCode="Botrule Rrule" valign="top">2%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0-90 (N = 373)</td><td align="left" styleCode="Botrule Rrule" valign="top">47%</td><td align="left" styleCode="Botrule Rrule" valign="top">51%</td><td align="left" styleCode="Botrule Rrule" valign="top">2%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0-180 (N = 377)</td><td align="left" styleCode="Botrule Rrule" valign="top">56%</td><td align="left" styleCode="Botrule Rrule" valign="top">42%</td><td align="left" styleCode="Botrule Rrule" valign="top">2%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0-365 (N = 380)</td><td align="left" styleCode="Botrule Rrule" valign="top">63%</td><td align="left" styleCode="Botrule Rrule" valign="top">36%</td><td align="left" styleCode="Botrule Rrule" valign="top">1%</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top">Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</td></tr></tbody></table>
"top">63%</td><td align="left" styleCode="Botrule Rrule" valign="top">36%</td><td align="left" styleCode="Botrule Rrule" valign="top">1%</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top">Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</td></tr></tbody></table> <table ID="t24" width="100%"><caption>Table 24. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2)</caption><col width="33.333%" align="left"/><col width="33.333%" align="left"/><col width="33.333%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">1. 95% confidence interval calculated using Fisher's Exact Test.</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Tacrolimus/MMF (N = 212)</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine/MMF (N = 212)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Overall Failure</td><td align="left" styleCode="Botrule Rrule" valign="top">32 (15.1%)</td><td align="left" styleCode="Botrule Rrule" valign="top">36 (17.0%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Components of efficacy failure</td><td align="left" styleCode="Botrule Rrule" valign="top"/><td align="left" styleCode="Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">BPAR</td><td align="left" styleCode="Botrule Rrule" valign="top">16 (7.5%)</td><td align="left" styleCode="Botrule Rrule" valign="top">29 (13.7%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Graft loss excluding death</td><td align="left" styleCode="Botrule Rrule" valign="top">6 (2.8%)</td><td align="left" styleCode="Botrule Rrule" valign="top">4 (1.9%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Mortality</td><td align="left" styleCode="Botrule Rrule" valign="top">9 (4.2%)</td><td align="left" styleCode="Botrule Rrule" valign="top">5 (2.4%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Lost to follow-up</td><td align="left" styleCode="Botrule Rrule" valign="top">4 (1.9%)</td><td align="left" styleCode="Botrule Rrule" valign="top">1 (0.5%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Treatment Difference of efficacy failure compared to Tacrolimus/MMF group (95% CI <content styleCode="italics"><sup>1</sup></content>) </td><td align="left" styleCode="Botrule Rrule" valign="top"/><td align="left" styleCode="Botrule Rrule" valign="top"> 1.9% (-5.2%, 9.0%) </td></tr></tbody></table>
Rrule" valign="top">Treatment Difference of efficacy failure compared to Tacrolimus/MMF group (95% CI <content styleCode="italics"><sup>1</sup></content>) </td><td align="left" styleCode="Botrule Rrule" valign="top"/><td align="left" styleCode="Botrule Rrule" valign="top"> 1.9% (-5.2%, 9.0%) </td></tr></tbody></table> <table ID="t25" width="100%"><caption>Table 25. Tacrolimus Whole Blood Trough Concentration Range (Study 2)</caption><col width="23.700%" align="left"/><col width="76.300%" align="left"/><tfoot><tr><td colspan="2" align="left" valign="top"><paragraph styleCode="footnote">1. 10 to 90 <sup>th</sup>Percentile: range of C <sub>trough,Tac</sub>that excludes lowest 10% and highest 10% of C <sub>trough,Tac</sub>. </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Time</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Median (P10-P90</content><sup>1</sup><content styleCode="bold">) tacrolimus whole blood trough concentration range (nanogram/mL)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 30 (N = 174)</td><td align="left" styleCode="Botrule Rrule" valign="top">10.5 (6.3 – 16.8)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 60 (N = 179)</td><td align="left" styleCode="Botrule Rrule" valign="top">9.2 (5.9 – 15.3)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 120 (N = 176)</td><td align="left" styleCode="Botrule Rrule" valign="top">8.3 (4.6 – 13.3)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 180 (N = 171)</td><td align="left" styleCode="Botrule Rrule" valign="top">7.8 (5.5 – 13.2)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 365 (N = 178)</td><td align="left" styleCode="Botrule Rrule" valign="top">7.1 (4.2 – 12.4)</td></tr></tbody></table>
e" valign="top">Day 180 (N = 171)</td><td align="left" styleCode="Botrule Rrule" valign="top">7.8 (5.5 – 13.2)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Day 365 (N = 178)</td><td align="left" styleCode="Botrule Rrule" valign="top">7.1 (4.2 – 12.4)</td></tr></tbody></table> <table ID="t26" width="100%"><caption>Table 26. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2)</caption><col width="15.604%" align="left"/><col width="28.132%" align="left"/><col width="28.132%" align="left"/><col width="28.132%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">1. Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods.</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Time period (Days)</content></td><td colspan="3" align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Time-averaged MMF dose (g/day)</content><sup>1</sup></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top">Less than 2.0</td><td align="left" styleCode="Botrule Rrule" valign="top">2.0</td><td align="left" styleCode="Botrule Rrule" valign="top">Greater than 2.0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0-30 (N = 212)</td><td align="left" styleCode="Botrule Rrule" valign="top">25%</td><td align="left" styleCode="Botrule Rrule" valign="top">69%</td><td align="left" styleCode="Botrule Rrule" valign="top">6%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0-90 (N = 212)</td><td align="left" styleCode="Botrule Rrule" valign="top">41%</td><td align="left" styleCode="Botrule Rrule" valign="top">53%</td><td align="left" styleCode="Botrule Rrule" valign="top">6%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0-180 (N = 212)</td><td align="left" styleCode="Botrule Rrule" valign="top">52%</td><td align="left" styleCode="Botrule Rrule" valign="top">41%</td><td align="left" styleCode="Botrule Rrule" valign="top">7%</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">0-365 (N = 212)</td><td align="left" styleCode="Botrule Rrule" valign="top">62%</td><td align="left" styleCode="Botrule Rrule" valign="top">34%</td><td align="left" styleCode="Botrule Rrule" valign="top">4%</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top">Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</td></tr></tbody></table>
16 HOW SUPPLIED/STORAGE AND HANDLING 16.2 Tacrolimus Injection (for Intravenous infusion only) Unit of Sale Concentration Each NDC 14789-135-05 Carton containing 10 vials 5 mg/mL NDC 14789-135-07 1 mL Single use vial 5 mg/mL (equivalent of 5 mg of anhydrous tacrolimus USP per mL) supplied as a sterile solution in a 1 mL vial, in a carton of 10 vials. Store and Dispense Store between 5°C and 25°C (41°F and 77°F). 16.4 Handling and Disposal Tacrolimus can cause fetal harm. Wearing disposable gloves is recommended during dilution of the injection in the hospital and when wiping any spills. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures 1 .
<table width="100%"><col width="33.333%" align="left"/><col width="33.333%" align="left"/><col width="33.333%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Unit of Sale</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Concentration</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Each</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">NDC 14789-135-05 Carton containing 10 vials </td><td align="left" styleCode="Botrule Rrule" valign="top">5 mg/mL</td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 14789-135-07 1 mL Single use vial </td></tr></tbody></table>
17 PATIENT COUNSELING INFORMATION 17.1 Administration Advise the patient or caregiver to: Not to eat grapefruit or drink grapefruit juice in combination with tacrolimus [see Drug Interactions ( 7.2 )]. 17.2 Development of Lymphoma and Other Malignancies Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Warnings and Precautions ( 5.1 )] . 17.3 Increased Risk of Infection Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Warnings and Precautions ( 5.2 )] . 17.4 New Onset Diabetes After Transplant Inform patients that tacrolimus can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst, or hunger [see Warnings and Precautions ( 5.4 )] . 17.5 Nephrotoxicity Inform patients that tacrolimus injection can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions ( 5.5 )] . 17.6 Neurotoxicity Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions ( 5.6 )] . 17.7 Hyperkalemia Inform patients that tacrolimus injection can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions ( 5.7 )] . 17.8 Hypertension Inform patients that tacrolimus can cause high blood pressure which may require treatment with antihypertensive therapy. Advise patients to monitor their blood pressure [see Warnings and Precautions ( 5.8 )] . 17.9 Thrombotic Microangiopathy Inform patients that tacrolimus can cause blood clotting problems. The risk of this occurring increases when patients take tacrolimus and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria. [see Warnings and Precautions ( 5.16 )] 17.10 Drug Interactions Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription medicines and nonprescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice [see Drug Interactions ( 7 )]. 17.11 Pregnancy, Lactation and Infertility Inform women of childbearing potential that tacrolimus can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations ( 8.1 , 8.2 , 8.3 )].
al that tacrolimus can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations ( 8.1 , 8.2 , 8.3 )]. Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ [see Use in Specific Populations ( 8.1 )] . Based on animal studies, tacrolimus may affect fertility in males and females [see Nonclinical Toxicology ( 13.1 )]. 17.12 Myocardial Hypertrophy Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure). 17.13 Immunizations Inform patients that Tacrolimus can interfere with the usual response to immunizations and that they should avoid live vaccines . [see Warnings and Precautions ( 5.14 )] . Manufactured in the USA for: Nexus Pharmaceuticals, LLC Lincolnshire, IL 60069 USA NEXUS PHARMACEUTICALS TACPI01USR01 Revised: 2/2025