Tacrolimus

Tacrolimus Manufacturers

• Major Pharmaceuticals
  

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  Tacrolimus | Major Pharmaceuticals

  

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  2.1 Dosage in Adult Kidney, Liver, or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. 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. For blood concentration monitoring details see Dosage and Administration ( 2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults * 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)].  Patient Population  

  Recommended Tacrolimus Capsules Initial

  Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours  Observed Tacrolimus Whole Blood Trough Concentrations  Adult kidney transplant patients      In combination with azathioprine  

  0.2 mg/kg/day

   

  month 1 to 3: 7 to 20 ng/mL

  month 4 to 12: 5 to 15 ng/mL

   In combination with MMF/IL-2 receptor antagonist *  

  0.1 mg/kg/day

   

  month 1 to 12: 4 to 11 ng/mL

   Adult liver transplant patients  0.10 to 0.15 mg/kg/day  month 1 to 12: 5 to 20 ng/mL  Adult heart transplant patients  0.075 mg/kg/day  

  month 1 to 3 : 10 to 20 ng/mL

  month ≥4: 5 to 15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsules dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients ( Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race  Time After Transplant  

  Caucasian

  n=114  

  Black

  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

  Initial Dose – Injection
  Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  The observed trough concentrations described above pertain to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous IV 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.

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see Warnings and Precautions ( 5.11)]

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration ( 2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children  Patient Population  

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours  Observed Tacrolimus Whole Blood Trough Concentrations  Pediatric liver transplant patients  0.15 to 0.20 mg/kg/day  Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to 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.

  2.4 Dosage Adjustments in 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 ( 2.1), Use in Specific Populations ( 8.7) and Clinical Pharmacology ( 12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3[see Dosage and Administration ( 2.1, 2.2)] ; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration ( 2.1)].

  It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see Clinical Pharmacology ( 12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions ( 7.2)].
  

  Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

  2.1 Dosage in Adult Kidney, Liver, or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. 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. For blood concentration monitoring details see Dosage and Administration ( 2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults * 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)].  Patient Population  

  Recommended Tacrolimus Capsules Initial

  Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours  Observed Tacrolimus Whole Blood Trough Concentrations  Adult kidney transplant patients      In combination with azathioprine  

  0.2 mg/kg/day

   

  month 1 to 3: 7 to 20 ng/mL

  month 4 to 12: 5 to 15 ng/mL

   In combination with MMF/IL-2 receptor antagonist *  

  0.1 mg/kg/day

   

  month 1 to 12: 4 to 11 ng/mL

   Adult liver transplant patients  0.10 to 0.15 mg/kg/day  month 1 to 12: 5 to 20 ng/mL  Adult heart transplant patients  0.075 mg/kg/day  

  month 1 to 3 : 10 to 20 ng/mL

  month ≥4: 5 to 15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsules dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients ( Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race  Time After Transplant  

  Caucasian

  n=114  

  Black

  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

  Initial Dose – Injection
  Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  The observed trough concentrations described above pertain to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous IV 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.

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see Warnings and Precautions ( 5.11)]

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration ( 2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children  Patient Population  

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours  Observed Tacrolimus Whole Blood Trough Concentrations  Pediatric liver transplant patients  0.15 to 0.20 mg/kg/day  Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to 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.

  2.4 Dosage Adjustments in 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 ( 2.1), Use in Specific Populations ( 8.7) and Clinical Pharmacology ( 12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3[see Dosage and Administration ( 2.1, 2.2)] ; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration ( 2.1)].

  It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see Clinical Pharmacology ( 12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions ( 7.2)].
  

  Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

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• Udl Laboratories, Inc.
  

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  Tacrolimus | Mylan Institutional Inc.

  

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  NOTE: Anaphylactic reactions have occurred with injectables containing castor oil derivatives. See WARNINGS.

  Tacrolimus Capsules Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations * Note: two divided doses, q12h † In a second smaller study, 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).

  Patient Population

  Recommended Initial Oral Dose*

  Typical Whole Blood Trough Concentrations

  Adult kidney transplant patients
       In combination with azathioprine

  0.2 mg/kg/day

  month 1 to 3: 7 to 20 ng/mL
  month 4 to 12: 5 to 15 ng/mL

       In combination with MMF/IL-2
       receptor antagonist†

  0.1 mg/kg/day

  month 1 to 12: 4 to 11 ng/mL

  Adult liver transplant patients

  0.10 to 0.15 mg/kg/day

  month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplant patients

  0.15 to 0.20 mg/kg/day

  month 1 to 12: 5 to 20 ng/mL

  Liver Transplantation

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion. The recommended starting oral dose of tacrolimus capsules is 0.10 to 0.15 mg/kg/day administered in two divided daily doses every 12 hours. Coadministered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. (See Drugs that May Alter Tacrolimus Concentrations.)

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post transplant.

  Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Liver Transplantation below.

  Kidney Transplantation

  The recommended starting oral dose of tacrolimus (administered every 12 hours in two divided doses) is 0.2 mg/kg/day when used in combination with azathioprine or 0.1 mg/kg/day when used in combination with MMF and IL-2 receptor antagonist (see CLINICAL STUDIES). The initial dose of tacrolimus may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated for example by a serum creatinine ≤ 4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Kidney Transplantation below.

  The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients.

  Time After
  Transplant

  Caucasian
  n = 114

  Black
  n = 56

   

  Dose (mg/kg)

  Trough
  Concentrations
  (ng/mL)

  Dose (mg/kg)

  Trough
  Concentrations
  (ng/mL)

  Day 7

  0.18

  12

  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

  Pediatric Patients

  Pediatric liver transplantation patients without preexisting renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in pediatric patients at a starting IV dose of 0.03 to 0.05 mg/kg/day and a starting oral dose of 0.15 to 0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney transplantation patients is limited.

  Patients with Hepatic or Renal Dysfunction

  Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Pugh ≥ 10) may require lower doses of tacrolimus. Close monitoring of blood concentrations is warranted.

  Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended IV and oral dosing ranges. Further reductions in dose below these ranges may be required. Tacrolimus therapy usually should be delayed up to 48 hours or longer in patients with postoperative oliguria.

  Conversion from One Immunosuppressive Regimen to Another

  Tacrolimus capsules 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.

  Blood Concentration 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.

  Two methods have been used for the assay of tacrolimus, a microparticle enzyme immunoassay (MEIA) and ELISA. Both methods have the same monoclonal antibody for tacrolimus. 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) anti-coagulant. Heparin anti-coagulation 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; if samples are to be kept longer they should be deep frozen at -20° C for up to 12 months.

  Liver Transplantation

  Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from Phase II and III studies of liver transplant patients have shown an increasing incidence of adverse events 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 often are maintained at the low end of this target range.

  Data from the U.S. clinical trial show that tacrolimus whole blood concentrations, as measured by ELISA, were most variable during the first week post transplantation. After this early period, 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.

  Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus document and several position papers regarding the therapeutic monitoring of tacrolimus from the 1995 International Consensus Conference on Immunosuppressive Drugs. Refer to these manuscripts for further discussions of tacrolimus monitoring.

  Kidney Transplantation

  Data from a Phase 3 study of tacrolimus in conjunction with azathioprine indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx® were most variable during the first week of dosing. 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 one year.

  In a separate clinical trial of tacrolimus in conjunction with MMF and daclizumab, approximately 80% of patients maintained tacrolimus whole blood concentrations between 4 to 11 ng/mL through one year post transplant.

  In another clinical trial of tacrolimus in conjunction with MMF and basiliximab, approximately 80% of patients maintained tacrolimus whole trough blood concentrations between 6 to 16 ng/mL during month 1 to 3 and, then, between 5 to 12 ng/mL from month 4 through one year.

  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.

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• Kaiser Foundation Hospitals
  

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  Tacrolimus | Kaiser Foundation Hospitals

  

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  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation.

  Summary of Initial Oral Dosage Recommendations and Typical Whole Blood Trough Concentrations *Note: two divided doses, q12h **In a second smaller study, 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). Patient Population Recommended Initial Oral Dose* Typical Whole Blood Trough Concentrations

  Adult kidney transplant patients

  In combination with azathioprine

  0.2 mg/kg/day

  month 1-3: 7-20 ng/mL month 4-12: 5-15 ng/mL

  In combination with MMF/IL-2

  receptor antagonist ** 0.1 mg/kg/day month 1-12: 4-11 ng/mL Adult liver transplant patients 0.10-0.15 mg/kg/day month 1-12: 5-20 ng/mL Pediatric liver transplant patients 0.15-0.20 mg/kg/day month 1-12: 5-20 ng/mL Liver Transplantation

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. The recommended starting oral dose of tacrolimus capsules is 0.1 to 0.15 mg/kg/day administered in two divided daily doses every 12 hours. Co-administered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. (See Drugs that May Alter Tacrolimus Concentrations).

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

  Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Liver Transplantation below.

  Kidney Transplantation

  The recommended starting oral dose of tacrolimus (administered every 12 hours in two divided doses) is 0.2 mg/kg/day when used in combination with azathioprine or 0.1 mg/kg/day when used in combination with MMF and IL-2 receptor antagonist (see CLINICAL STUDIES ). The initial dose of tacrolimus may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated for example by a serum creatinine ≤ 4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring Kidney Transplantationbelow.

  The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients.

  Time After Transplant Caucasian n=114 Black n=56 Dose (mg/kg) Trough Concentrations (ng/mL) Dose (mg/kg) Trough Concentrations (ng/mL) Day 7 0.18 12 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 Pediatric Patients

   Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in pediatric patients at a starting oral dose of 0.15-0.2 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney transplantation patients is limited.

  Patients with Hepatic or Renal Dysfunction

  Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Pugh ≥ 10) may require lower doses of tacrolimus. Close monitoring of blood concentrations is warranted.

  Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended oral dosing ranges. Further reductions in dose below these ranges may be required. Tacrolimus therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria.

  Conversion from One Immunosuppressive Regimen to Another

  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.

  Blood Concentration 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 posttransplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies.

  Two methods have been used for the assay of tacrolimus, a microparticle enzyme immunoassay (MEIA) and ELISA. Both methods have the same monoclonal antibody for tacrolimus. 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; if samples are to be kept longer they should be deep frozen at -20° C for up to 12 months.

  Liver Transplantation

  Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from Phase II and III studies of liver transplant patients have shown an increasing incidence of adverse events 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 often are maintained at the low end of this target range.

  Data from the U.S. clinical trial show that tacrolimus whole blood concentrations, as measured by ELISA, were most variable during the first week post-transplantation. After this early period, 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.

  Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus document and several position papers regarding the therapeutic monitoring of tacrolimus from the 1995 International Consensus Conference on Immunosuppressive Drugs. Refer to these manuscripts for further discussions of tacrolimus monitoring.

  Kidney Transplantation

  Data from a Phase 3 study of tacrolimus in conjunction with azathioprine indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx® were most variable during the first week of dosing. During the first three 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.

  In a separate clinical trial of tacrolimus in conjunction with MMF and daclizumab, approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant.

  In another clinical trial of tacrolimus in conjunction with MMF and basiliximab, approximately 80% of patients maintained tacrolimus whole trough blood concentrations between 6-16 ng/mL during month 1-3 and, then, between 5-12 ng/mL from month 4 through 1 year.

  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.

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  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation.

  Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations *Note: two divided doses, q12h **In a second smaller study, 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). Patient Population Recommended Initial Oral Dosage* Observed Whole Blood Trough Concentrations

  Adult kidney transplant patients

  In combination with azathioprine

  0.2 mg/kg/day

  month 1-3: 7-20 ng/mL month 4-12: 5-15 ng/mL

  In combination with MMF/IL-2

  receptor antagonist ** 0.1 mg/kg/day month 1-12: 4-11 ng/mL Adult liver transplant patients 0.10-0.15 mg/kg/day month 1-12: 5-20 ng/mL Pediatric liver transplant patients 0.15-0.20 mg/kg/day month 1-12: 5-20 ng/mL Liver Transplantation

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. The recommended starting oral dose of tacrolimus capsules is 0.1 to 0.15 mg/kg/day administered in two divided daily doses every 12 hours. Co-administered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. (See Drugs that May Alter Tacrolimus Concentrations).

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

  Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Liver Transplantation below.

  Kidney Transplantation

  The recommended starting oral dose of tacrolimus (administered every 12 hours in two divided doses) is 0.2 mg/kg/day when used in combination with azathioprine or 0.1 mg/kg/day when used in combination with MMF and IL-2 receptor antagonist (see CLINICAL STUDIES ). The initial dose of tacrolimus may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated for example by a serum creatinine ≤ 4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration MonitoringKidney Transplantationbelow.

  The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients.

  Time After Transplant Caucasian n=114 Black n=56 Dose (mg/kg) Trough Concentrations (ng/mL) Dose (mg/kg) Trough Concentrations (ng/mL) Day 7 0.18 12 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 Pediatric Patients

   Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in pediatric patients at a starting oral dose of 0.15-0.2 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney transplantation patients is limited.

  Patients with Hepatic or Renal Dysfunction

  Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Pugh ≥ 10) may require lower doses of tacrolimus. Close monitoring of blood concentrations is warranted.

  Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended oral dosing ranges. Further reductions in dose below these ranges may be required. Tacrolimus therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria.

  Conversion from One Immunosuppressive Regimen to Another

  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.

  Blood Concentration 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 posttransplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies.

  Two methods have been used for the assay of tacrolimus, a microparticle enzyme immunoassay (MEIA) and ELISA. Both methods have the same monoclonal antibody for tacrolimus. 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; if samples are to be kept longer they should be deep frozen at -20° C for up to 12 months.

  Liver Transplantation

  Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from Phase II and III studies of liver transplant patients have shown an increasing incidence of adverse events 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 often are maintained at the low end of this target range.

  Data from the U.S. clinical trial show that tacrolimus whole blood concentrations, as measured by ELISA, were most variable during the first week post-transplantation. After this early period, 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.

  Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus document and several position papers regarding the therapeutic monitoring of tacrolimus from the 1995 International Consensus Conference on Immunosuppressive Drugs. Refer to these manuscripts for further discussions of tacrolimus monitoring.

  Kidney Transplantation

  Data from a Phase 3 study of tacrolimus in conjunction with azathioprine indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx® were most variable during the first week of dosing. During the first three 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.

  In a separate clinical trial of tacrolimus in conjunction with MMF and daclizumab, approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant.

  In another clinical trial of tacrolimus in conjunction with MMF and basiliximab, approximately 80% of patients maintained tacrolimus whole trough blood concentrations between 6-16 ng/mL during month 1-3 and, then, between 5-12 ng/mL from month 4 through 1 year.

  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.

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  2.1 Dosage in Adult Kidney, Liver, or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. 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. For blood concentration monitoring details see Dosage and Administration (2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults * 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)].

  Patient Population

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours

  Observed Tacrolimus Whole Blood Trough Concentrations

  Adult kidney transplant patients

       In combination with azathioprine

  0.2 mg/kg/day

  month 1 to 3: 7 to 20 ng/mL

  month 4 to 12: 5 to 15 ng/mL

       In combination with MMF/IL-2 receptor antagonist*

  0.1 mg/kg/day

  month 1 to 12: 4 to 11 ng/mL

  Adult liver transplant patients

  0.10 to 0.15 mg/kg/day

  month 1 to 12: 5 to 20 ng/mL

  Adult heart transplant patients

  0.075 mg/kg/day

  month 1 to 3: 10 to 20 ng/mL month ≥ 4: 5 to 15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race

  Time After Transplant

  Caucasian
  n = 114

  Black
  n = 56

  Dose
  (mg/kg)

  Trough Concentrations (ng/mL)

  Dose
  (mg/kg)

  Trough Concentrations (ng/mL)

  Day 7

  0.18

  12

  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

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see Warnings and Precautions (5.11)].

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration (2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children

  Patient Population

  Recommended Tacrolimus Capsules Initial Oral Dosage
  Note: daily doses should be administered as two divided doses, every 12 hours

  Observed Tacrolimus Whole Blood Trough Concentrations

  Pediatric liver transplant patients

  0.15 to 0.20 mg/kg/day

  Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to 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.

  2.4 Dosage Adjustments in 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 (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see Dosage and Administration (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration (2.1)].

  It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see Clinical Pharmacology (12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions (7.2)].

  Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus capsules is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

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  NOTE: Anaphylactic reactions have occurred with injectables containing castor oil derivatives. See WARNINGS.

  Tacrolimus capsules

  Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations  Patient Population  Recommended Initial Oral Dosagea  Observed Whole Blood Trough Concentrations   a) Note: two divided doses, q12h   b) In a second smaller study, 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).  Adult kidney transplant patients      In combination with azathioprine  0.2 mg/kg/day  month 1 to 3: 7 to 20 ng/mL      month 4 to 12: 5 to 15 ng/mL  In combination with MMF/IL-2 receptor antagonistb  0.1 mg/kg/day  month 1 to 12: 4 to 11 ng/mL  Adult liver transplant patients  0.10 to 0.15 mg/kg/day  month 1 to 12: 5 to 20 ng/mL  Pediatric liver transplant patients  0.15 to 0.20 mg/kg/day  month 1 to 12: 5 to 20 ng/mL

  Liver Transplantation

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion. The recommended starting oral dose of tacrolimus capsules is 0.10 to 0.15 mg/kg/day administered in two divided daily doses every 12 hours. Coadministered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. (See Drugs that May Alter Tacrolimus Concentrations).

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

  Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Liver Transplantation below.

  Kidney Transplantation

  The recommended starting oral dose of tacrolimus (administered every 12 hours in two divided doses) is 0.2 mg/kg/day when used in combination with azathioprine or 0.1 mg/kg/day when used in combination with MMF and IL-2 receptor antagonist (see CLINICAL STUDIES). The initial dose of tacrolimus may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated for example by a serum creatinine ≤ 4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Kidney Transplantation below.

  The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients.

   Time After Transplant  Caucasian
  n=114  Black
  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

  Pediatric Patients

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in pediatric patients at a starting IV dose of 0.03 to 0.05 mg/kg/day and a starting oral dose of 0.15 to 0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney transplantation patients is limited.

  Patients with Hepatic or Renal Dysfunction

  Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Pugh ≥ 10) may require lower doses of tacrolimus. Close monitoring of blood concentrations is warranted.

  Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended IV and oral dosing ranges. Further reductions in dose below these ranges may be required. Tacrolimus therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria.

  Conversion from One Immunosuppressive Regimen to Another

  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.

  Blood Concentration 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.

  Two methods have been used for the assay of tacrolimus, a microparticle enzyme immunoassay (MEIA) and ELISA. Both methods have the same monoclonal antibody for tacrolimus. 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) anti-coagulant. Heparin anti-coagulation 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; if samples are to be kept longer they should be deep frozen at -20° C for up to 12 months.

  Liver Transplantation

  Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from Phase II and III studies of liver transplant patients have shown an increasing incidence of adverse events 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 often are maintained at the low end of this target range.

  Data from the U.S. clinical trial show that tacrolimus whole blood concentrations, as measured by ELISA, were most variable during the first week post-transplantation. After this early period, 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.

  Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus document and several position papers regarding the therapeutic monitoring of tacrolimus from the 1995 International Consensus Conference on Immunosuppressive Drugs. Refer to these manuscripts for further discussions of tacrolimus monitoring.

  Kidney Transplantation

  Data from a Phase 3 study of tacrolimus in conjunction with azathioprine indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx®** were most variable during the first week of dosing. During the first three 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.

  In a separate clinical trial of tacrolimus in conjunction with MMF and daclizumab, approximately 80% of patients maintained tacrolimus whole blood concentrations between 4 to 11 ng/mL through 1 year post-transplant.

  In another clinical trial of tacrolimus in conjunction with MMF and basiliximab, approximately 80% of patients maintained tacrolimus whole trough blood concentrations between 6 to 16 ng/mL during month 1 to 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.

  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.

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  2.1 Dosage in Adult Kidney or Liver Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney or liver transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of tacrolimus capsules should be administered no sooner than 6 hours after transplantation in the liver 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. For blood concentration monitoring details see Dosage and Administration (2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults

  a) 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)].

  Patient Population Recommended Tacrolimus Capsules Initial Oral Dosage
  Note: daily doses should be
  administered as two divided
  doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Adult kidney transplant patients
  
  In combination with azathioprine
  
  
  In combination with MMF/IL-2 receptor antagonista
  
  0.2 mg/kg/day
  
  
  0.1 mg/kg/day
  
  month 1 to 3 : 7 to 20 ng/mL
  month 4 to 12 : 5 to 15 ng/mL
  
  month 1 to 12 : 4 to 11 ng/mL
  Adult liver transplant patients 0.10 to 0.15 mg/kg/day month 1 to 12 : 5 to 20 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsules dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race Time After
  Transplant Caucasian
  n=114 Black
  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

  Initial Dose – Injection

  Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  The observed trough concentrations described above pertain to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous IV 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.

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see Warnings and Precautions (5.11)].

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration (2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children Patient Population Recommended Tacrolimus Capsules Initial Oral Dosage
  Note: daily doses should be
  administered as two divided doses,
  every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Pediatric liver transplant patients 0.15 to 0.20 mg/kg/day Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver 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.

  2.4 Dosage Adjustments in 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 (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see Dosage and Administration (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration (2.1)].

  It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see Clinical Pharmacology (12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions (7.2)].

  Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

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  2.1 Dosage in Adult Kidney, Liver. or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. 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. For blood concentration monitoring details see Dosage and Administration (2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults

  Patient Population Recommended Tacrolimus Initial Oral Dosage Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Adult kidney transplant patients 
  In combination with azathioprine   
  In combination with MMF/IL-2 receptor antagonist a   
  
  0.2 mg/kg/day   
  
  0.1 mg/kg/day
  
  month 1 to 3: 7 to 20 ng/mL
  month 4 to 12: 5 to 15 ng/mL 
  month 1 to 12: 4 to 11 ng/mL Adult liver transplant patients 0.10 to 0.15 mg/kg/day month 1 to 12: 5 to 20 ng/mL Adult heart transplant patients 0.075 mg/kg/day month 1 to 3: 10 to 20 ng/mL
  month ≥4: 5 to 15 ng/mL

  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 [seeClinical Studies (14.1)]. Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsule dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race

  Time After Transplant Caucasian
  n=114 Black
  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

  Initial Dose – Injection

  Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules.Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion. 

  The observed trough concentrations described above pertain to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous IV 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.  

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see Warnings and Precautions (5.11)].

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration (2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children

  Patient Population Recommended Tacrolimus Initial Oral Dosage Observed Tacrolimus Whole Blood Trough Concentrations   Note: daily doses should be administered as two divided doses, every 12 hours   Pediatric liver transplant patients 0.15 to 0.20 mg/kg/day Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver 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.

  2.4 Dosage Adjustments in 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 (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see Dosage and Administration (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration (2.1)].

  It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see Clinical Pharmacology (12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions (7.2)].

  Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus capsules is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

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  Tacrolimus | Arbor Pharmaceuticals Ireland Limited

  

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  2.1 Dosing Information

  The recommended starting dose of Edarbyclor is 40/12.5 mg taken orally once daily. Most of the antihypertensive effect is apparent within 1 to 2 weeks. The dosage may be increased to 40/25 mg after 2 to 4 weeks as needed to achieve blood pressure goals. Edarbyclor doses above 40/25 mg are probably not useful.

  Edarbyclor may be used to provide additional blood pressure lowering for patients not adequately controlled on ARB or diuretic monotherapy treatment. Patients not controlled with azilsartan medoxomil 80 mg may have an additional systolic / diastolic clinic blood pressure reduction of 13/6 mm Hg when switched to Edarbyclor 40/12.5 mg. Patients not controlled with chlorthalidone 25 mg may have an additional clinic blood pressure reduction of 10/7 mm Hg when switched to Edarbyclor 40/12.5 mg.

  Edarbyclor may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals.

  Patients titrated to the individual components (azilsartan medoxomil and chlorthalidone) may instead receive the corresponding dose of Edarbyclor.

  Edarbyclor may be taken with or without food [see Clinical Pharmacology (12.3)].

  Edarbyclor may be administered with other antihypertensive agents as needed.

  2.2 Prior to Dosing

  Correct any volume depletion prior to administration of Edarbyclor, particularly in patients with impaired renal function or those treated with high doses of diuretics [see Warnings and Precautions (5.2)].

  Patients who experience dose-limiting adverse reactions on chlorthalidone may be switched to Edarbyclor, initially with a lower dose of chlorthalidone [see Warnings and Precautions (5.4)].

  2.3 Handling Instructions

  As Edarbyclor is moisture sensitive, dispense and store Edarbyclor in its original container to protect Edarbyclor from light and moisture.

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  2.1 Dosage in Adult Kidney, Liver. or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. 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. For blood concentration monitoring details see Dosage and Administration (2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults

  Patient Population

  Recommended Tacrolimus Initial Oral Dosage Note: daily doses should be administered as two divided doses, every 12 hours

  Observed Tacrolimus Whole Blood Trough Concentrations

  Adult kidney transplant patients 
  In combination with azathioprine   
  In combination with MMF/IL-2 receptor antagonist a

    
  
  0.2 mg/kg/day   
  
  0.1 mg/kg/day

  
  
  month 1 to 3: 7 to 20 ng/mL
  month 4 to 12: 5 to 15 ng/mL 
  month 1 to 12: 4 to 11 ng/mL

  Adult liver transplant patients

  0.10 to 0.15 mg/kg/day

  month 1 to 12: 5 to 20 ng/mL

  Adult heart transplant patients

  0.075 mg/kg/day

  month 1 to 3: 10 to 20 ng/mL
  month ≥4: 5 to 15 ng/mL

  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 [seeClinical Studies (14.1)]. Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsule dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race

  Time After Transplant

  Caucasian
  n=114

  Black
  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

  Initial Dose – Injection

  Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules.Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion. 

  The observed trough concentrations described above pertain to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous IV 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.  

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see Warnings and Precautions (5.11)].

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration (2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children

  Patient Population

  Recommended Tacrolimus Initial Oral Dosage

  Observed Tacrolimus Whole Blood Trough Concentrations

   

  Note: daily doses should be administered as two divided doses, every 12 hours

   

  Pediatric liver transplant patients

  0.15 to 0.20 mg/kg/day

  Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver 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.

  2.4 Dosage Adjustments in 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 (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see Dosage and Administration (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration (2.1)].

  It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see Clinical Pharmacology (12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions (7.2)].

  Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus capsules is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

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  2.1 Dosage in Adult Kidney, Liver or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of Tacrolimus Capsules USP 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 USP may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see Dosage and Administration (2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults Patient Population Recommended Tacrolimus
  Capsules USP Initial Oral
  Dosage
  Note: daily doses should be
  administered as two divided
  doses, every 12 hours Observed Tacrolimus Whole
  Blood Trough Concentrations Adult kidney transplant patients
  
  In combination with azathioprine
  
  
  In combination with MMF/IL-2 receptor
  antagonist a
  
  0.2 mg/kg/day
  
  
  0.1 mg/kg/day
  
  month 1-3: 7-20 ng/mL
  month 4-12: 5-15 ng/mL
  
  month 1-12: 4-11 ng/mL Adult liver transplant patients 0.10-0.15 mg/kg/day month 1-12: 5-20 ng/mL Adult heart transplant patients 0.075 mg/kg/day month 1-3: 10-20 ng/mL
  month ≥4: 5-15 ng/mL

  a) 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)].

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race Time After Transplant Caucasian
  n=114 Black
  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 Initial Dose - Injection

  Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Tacrolimus Capsules USP. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of Tacrolimus Capsules USP, usually within 2-3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion.

  The observed trough concentrations described above pertain to oral administration of Tacrolimus Capsules USP only; while monitoring tacrolimus concentrations in patients receiving Tacrolimus injection as a continuous IV 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.

  The recommended starting dose of Tacrolimus injection is 0.03-0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as Tacrolimus injection [see Warnings and Precautions (5.11)].

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration (2.6). If necessary, pediatric patients may start on an IV dose of 0.03-0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children Patient Population Recommended Tacrolimus Capsules USP Initial Oral Dosage
  Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Pediatric liver transplant patients 0.15- 0.20 mg/kg/day Month 1-12: 5-20 ng/ mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to dosing Tacrolimus Capsules USP 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 USP 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.

  2.4 Dosage Adjustments in 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 Capsules USP 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 (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with Tacrolimus Capsules USP if possible.Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see Dosage and Administration (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration (2.1)].

  It is important to take Tacrolimus Capsules USP consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus [see Clinical Pharmacology (12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus [see Drug Interactions (7.2)].

  Tacrolimus Capsules USP should not be used simultaneously with cyclosporine. Tacrolimus Capsules USP 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.

  In patients unable to take oral Tacrolimus Capsules USP, therapy may be initiated with Tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral Tacrolimus Capsules USP is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

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  2.1 Dosage in Adult Kidney, Liver or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of tacrolimus capsules, USP 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, USP may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see DOSAGE AND ADMINISTRATION (2.6 ).

  Table 1 Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults

  * 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 months 1 to 3 and 5 to 12 ng/mL during months 4 to 12 [see CLINICAL STUDIES (14.1)].

  Patient Population

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours

  Observed Tacrolimus Whole Blood Trough Concentrations

  Adult kidney transplant patients

  In combination with azathioprine

  0.2 mg/kg/day

  month 1 to 3: 7 to 20 ng/mL

  month 4 to 12: 5 to 15 ng/mL

  In combination with MMF/IL-2
  receptor antagonist*

  0.1 mg/kg/day

  month 1 to 12: 4 to 11 ng/mL

  Adult liver transplant patients

  0.10 to 0.15 mg/kg/day

  month 1 to 12: 5 to 20 ng/mL

  Adult heart transplant patients

  0.075 mg/kg/day

  month 1 to 3: 10 to 20 ng/mL

  month ≥4: 5 to 15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsules, USP dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).

  Table 2 Comparative Dose and Trough Concentrations Based on Race

  Time After Transplant

  Caucasian

  n=114

  Black

  n=56

  Dose

  (mg/kg)

  Trough Concentrations

  (ng/mL)

  Dose

  (mg/kg)

  Trough Concentrations (ng/mL)

  Day 7

  0.18

  12

  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

  Initial Dose – Injection

  Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules, USP. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, USP, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  The observed trough concentrations described above pertain to oral administration of tacrolimus capsules, USP only; while monitoring tacrolimus capsules concentrations in patients receiving tacrolimus injection as a continuous IV 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.

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see WARNINGS AND PRECAUTIONS (5.11)].

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see DOSAGE AND ADMINISTRATION (2.6 ). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3 Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children

  Patient Population

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours

  Observed Tacrolimus Whole Blood Trough Concentrations

  Pediatric liver transplant patients

  0.15 to 0.20 mg/kg/day

  Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus capsules, USP 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, USP 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.

  2.4 Dosage Adjustments in 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, USP. Close monitoring of blood concentrations is warranted.

  The use of tacrolimus capsules, USP 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 (2.1), USE IN SPECIFIC POPULATIONS (8.7) and CLINICAL PHARMACOLOGY (12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules, USP if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see DOSAGE AND ADMINISTRATION (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see DOSAGE AND ADMINISTRATION (2.1)].

  It is important to take tacrolimus capsules, USP consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules, USP [see CLINICAL PHARMACOLOGY (12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules, USP [see DRUG INTERACTIONS (7.2)]

  Tacrolimus capsules, USP should not be used simultaneously with cyclosporine. Tacrolimus capsules, USP or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules, USP or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, USP, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

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  There is currently no dosage information available for this product. We apologize for any inconvenience.

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  Tacrolimus | Tween Brands, Inc.

  

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  2.1 Dosage in Adult Kidney, Liver, or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of tacrolimus capsules, USP 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, USP may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see DOSAGE AND ADMINISTRATION (2.6 ).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults

  * 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 months 1 to 3 and 5 to 12 ng/mL during months 4 to 12 [see CLINICAL STUDIES (14.1)].

  Patient Population

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours

  Observed Tacrolimus Whole Blood Trough Concentrations

  Adult kidney transplant patients

  In combination with azathioprine

  0.2 mg/kg/day

  month 1 to 3: 7 to 20 ng/mL

  month 4 to 12: 5 to 15 ng/mL

  In combination with MMF/IL-2
  receptor antagonist*

  0.1 mg/kg/day

  month 1 to 12: 4 to 11 ng/mL

  Adult liver transplant patients

  0.10 to 0.15 mg/kg/day

  month 1 to 12: 5 to 20 ng/mL

  Adult heart transplant patients

  0.075 mg/kg/day

  month 1 to 3: 10 to 20 ng/mL

  month ≥4: 5 to 15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsules, USP dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race

  Time After Transplant

  Caucasian

  n=114

  Black

  n=56

  Dose

  (mg/kg)

  Trough Concentrations

  (ng/mL)

  Dose

  (mg/kg)

  Trough Concentrations (ng/mL)

  Day 7

  0.18

  12

  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

  Initial Dose – Injection

  Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules, USP. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, USP, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  The observed trough concentrations described above pertain to oral administration of tacrolimus capsules, USP only; while monitoring tacrolimus capsules concentrations in patients receiving tacrolimus injection as a continuous IV 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.

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection[see WARNINGS AND PRECAUTIONS (5.11)].

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see DOSAGE AND ADMINISTRATION (2.6 ). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children

  Patient Population

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours

  Observed Tacrolimus Whole Blood Trough Concentrations

  Pediatric liver transplant patients

  0.15 to 0.20 mg/kg/day

  Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus capsules, USP 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, USP 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.

  2.4 Dosage Adjustments in 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, USP. Close monitoring of blood concentrations is warranted.

  The use of tacrolimus capsules, USP 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 (2.1 ), USE IN SPECIFIC POPULATIONS (8.7) and CLINICAL PHARMACOLOGY (12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules, USP if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see DOSAGE AND ADMINISTRATION (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see DOSAGE AND ADMINISTRATION (2.1)].

  It is important to take tacrolimus capsules, USP consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see CLINICAL PHARMACOLOGY (12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules, USP [see DRUG INTERACTIONS (7.2)].

  Tacrolimus capsules, USP should not be used simultaneously with cyclosporine. Tacrolimus capsules, USP or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules, USP or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, USP, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

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  Tacrolimus | Accord Healthcare Inc.

  

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  2.1 Dosage in Adult Kidney, Liver, or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. 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. For blood concentration monitoring details see Dosage and Administration ( 2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults * 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)]. Patient Population

  Recommended Tacrolimus Capsules Initial

  Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Adult kidney transplant patients In combination with azathioprine

  0.2 mg/kg/day

  month 1 to 3: 7 to 20 ng/mL

  month 4 to 12: 5 to 15 ng/mL

  In combination with MMF/IL-2 receptor antagonist *

  0.1 mg/kg/day

  month 1 to 12: 4 to 11 ng/mL

  Adult liver transplant patients 0.10 to 0.15 mg/kg/day month 1 to 12: 5 to 20 ng/mL Adult heart transplant patients 0.075 mg/kg/day

  month 1 to 3 : 10 to 20 ng/mL

  month ≥4: 5 to 15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsules dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients ( Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race Time After Transplant

  Caucasian

  n=114

  Black

  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

  Initial Dose – Injection
  Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  The observed trough concentrations described above pertain to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous IV 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.

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see Warnings and Precautions ( 5.11)]

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration ( 2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children Patient Population

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Pediatric liver transplant patients 0.15 to 0.20 mg/kg/day Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to 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.

  2.4 Dosage Adjustments in 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 ( 2.1), Use in Specific Populations ( 8.7) and Clinical Pharmacology ( 12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3[see Dosage and Administration ( 2.1, 2.2)] ; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration ( 2.1)].

  It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see Clinical Pharmacology ( 12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions ( 7.2)].
  

  Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

  2.1 Dosage in Adult Kidney, Liver, or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. 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. For blood concentration monitoring details see Dosage and Administration ( 2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults * 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)]. Patient Population

  Recommended Tacrolimus Capsules Initial

  Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Adult kidney transplant patients In combination with azathioprine

  0.2 mg/kg/day

  month 1 to 3: 7 to 20 ng/mL

  month 4 to 12: 5 to 15 ng/mL

  In combination with MMF/IL-2 receptor antagonist *

  0.1 mg/kg/day

  month 1 to 12: 4 to 11 ng/mL

  Adult liver transplant patients 0.10 to 0.15 mg/kg/day month 1 to 12: 5 to 20 ng/mL Adult heart transplant patients 0.075 mg/kg/day

  month 1 to 3 : 10 to 20 ng/mL

  month ≥4: 5 to 15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsules dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients ( Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race Time After Transplant

  Caucasian

  n=114

  Black

  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

  Initial Dose – Injection
  Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  The observed trough concentrations described above pertain to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous IV 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.

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see Warnings and Precautions ( 5.11)]

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration ( 2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children Patient Population

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Pediatric liver transplant patients 0.15 to 0.20 mg/kg/day Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to 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.

  2.4 Dosage Adjustments in 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 ( 2.1), Use in Specific Populations ( 8.7) and Clinical Pharmacology ( 12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3[see Dosage and Administration ( 2.1, 2.2)] ; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration ( 2.1)].

  It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see Clinical Pharmacology ( 12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions ( 7.2)].
  

  Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  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. Observed whole blood trough concentrations 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) anti-coagulant. Heparin anti-coagulation 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.

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  Tacrolimus | Sagent Pharmaceuticals

  

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  Chlorothiazide Sodium for Injection, USP should be reserved for patients unable to take oral medication or for emergency situations.

  Therapy should be individualized according to patient response. Use the smallest dosage necessary to achieve the required response.

  Intravenous use in infants and children has been limited and is not generally recommended.

  When medication can be taken orally, therapy with chlorothiazide tablets or oral suspension may be substituted for intravenous therapy, using the same dosage schedule as for the parenteral route.

  Chlorothiazide Sodium for Injection, USP may be given slowly by direct intravenous injection or by intravenous infusion.

  Extravasation must be rigidly avoided. Do not give subcutaneously or intramuscularly.

  The usual adult dosage is 500 mg to 1 g once or twice a day. Many patients with edema respond to intermittent therapy, i.e., administration on alternate days or on three to five days each week. With an intermittent schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur.

  Directions for Reconstitution

  Use aseptic technique. Because Chlorothiazide Sodium for Injection, USP contains no preservative, a fresh solution should be prepared immediately prior to each administration, and the unused portion should be discarded.

  Add 18 mL of Sterile Water for Injection to the vial to form an isotonic solution for intravenous injection. Never add less than 18 mL. When reconstituted with 18 mL of Sterile Water, the final concentration of Chlorothiazide Sodium for Injection, USP is 28 mg per mL. The reconstituted solution is clear and essentially free from visible particles. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit. The solution is compatible with dextrose or sodium chloride solutions for intravenous infusion. Avoid simultaneous administration of solutions of chlorothiazide with whole blood or its derivatives.

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