Prograf

Prograf Manufacturers

• Rebel Distributors Corp
  

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  Prograf | Rebel Distributors Corp

  

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  Prograf injection (tacrolimus injection)

  For IV Infusion Only

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

  In patients unable to take oral Prograf capsules, therapy may be initiated with Prograf injection. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. The recommended starting dose of Prograf injection is 0.01 mg/kg/day (heart) or 0.03-0.05 mg/kg/day (liver, kidney) 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. Continuous IV infusion of Prograf injection should be continued only until the patient can tolerate oral administration of Prograf capsules.

  Preparation for Administration/Stability

  Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a PVC container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Due to the chemical instability of tacrolimus in alkaline media, Prograf injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).

  Prograf capsules (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 0.15-0.2 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

  In combination with MMF/IL-2 receptor

  antagonist †

  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 Pediatric liver transplant patients 0.15-0.20 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 Liver Transplantation

  It is recommended that patients initiate oral therapy with Prograf capsules if possible. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of Prograf 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 Prograf capsules is 0.10 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 Prograf 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 Prograf (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 Prograf 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 Heart Transplantation

  The recommended starting oral dose of Prograf is 0.075 mg/kg/day administered every 12 hours in two divided doses. If possible, initiating oral therapy with Prograf capsules is recommended. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of Prograf 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.

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Prograf 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: Heart Transplantationbelow.

  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 0.03-0.05 mg/kg/day and a starting oral dose of 0.15-0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney and heart 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 Prograf. 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. Prograf therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria.

  Conversion from One Immunosuppressive Regimen to Another

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

  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) 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 Prograf 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 Prograf 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 Prograf 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.

  Heart Transplantation

  Data from a European Phase 3 study indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx®  were most variable during the first week of dosing. From 1 week to 3 months post transplant, approximately 80% of patients maintained trough concentrations between 8-20 ng/mL and, from 3 months through 18 months post transplant, approximately 80% of patients maintained trough concentrations between 6-18 ng/mL.

  The relative risk of toxicity; for example, nephrotoxicity and post-transplant diabetes mellitus, is increased with higher trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity.

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• Cardinal Health
  

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  Prograf | Cardinal Health

  

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  Prograf injection (tacrolimus injection)

  For IV Infusion Only

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

  In patients unable to take oral Prograf capsules, therapy may be initiated with Prograf injection. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. The recommended starting dose of Prograf injection is 0.01 mg/kg/day (heart) or 0.03-0.05 mg/kg/day (liver, kidney) 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. Continuous IV infusion of Prograf injection should be continued only until the patient can tolerate oral administration of Prograf capsules.

  Preparation for Administration/Stability

  Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a PVC container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Due to the chemical instability of tacrolimus in alkaline media, Prograf injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).

  Prograf capsules (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 0.15-0.2 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

  In combination with MMF/IL-2 receptor

  antagonist †

  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 Pediatric liver transplant patients 0.15-0.20 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 Liver Transplantation

  It is recommended that patients initiate oral therapy with Prograf capsules if possible. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of Prograf 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 Prograf capsules is 0.10 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 Prograf 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 Prograf (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 Prograf 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 Heart Transplantation

  The recommended starting oral dose of Prograf is 0.075 mg/kg/day administered every 12 hours in two divided doses. If possible, initiating oral therapy with Prograf capsules is recommended. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of Prograf 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.

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Prograf 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: Heart Transplantationbelow.

  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 0.03-0.05 mg/kg/day and a starting oral dose of 0.15-0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney and heart 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 Prograf. 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. Prograf therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria.

  Conversion from One Immunosuppressive Regimen to Another

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

  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) 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 Prograf 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 Prograf 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 Prograf 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.

  Heart Transplantation

  Data from a European Phase 3 study indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx®  were most variable during the first week of dosing. From 1 week to 3 months post transplant, approximately 80% of patients maintained trough concentrations between 8-20 ng/mL and, from 3 months through 18 months post transplant, approximately 80% of patients maintained trough concentrations between 6-18 ng/mL.

  The relative risk of toxicity; for example, nephrotoxicity and post-transplant diabetes mellitus, is increased with higher trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity.

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• Aphena Pharma Solutions – Tennessee, Llc
  

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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 Prograf 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 Prograf 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 0.15-0.2 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)].

  Patient Population

  Recommended Prograf 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 1-3: 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

  Adult heart transplant patients

  0.075 mg/kg/day

  month 1-3: 10-20 ng/mL

  month ≥4: 5-15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Prograf 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

  Prograf injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Prograf capsules. Prograf injection should be discontinued as soon as the patient can tolerate oral administration of Prograf capsules, 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 Prograf only; while monitoring Prograf concentrations in patients receiving Prograf 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 Prograf 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 Prograf 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 Prograf 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 Prograf at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

  In kidney transplant patients with post-operative oliguria, the initial dose of Prograf should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery.

  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 Prograf. Close monitoring of blood concentrations is warranted.

  The use of Prograf in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with Prograf 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 Prograf capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Prograf [see Clinical Pharmacology (12.3)].

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

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

  In patients unable to take oral Prograf capsules, therapy may be initiated with Prograf injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral Prograf 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.

  2.7 Preparation for Intravenous Product

  Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a PVC container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Due to the chemical instability of tacrolimus in alkaline media, Prograf injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).

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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 Prograf 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 Prograf 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 0.15-0.2 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)].

  Patient Population

  Recommended Prograf 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 1-3: 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

  Adult heart transplant patients

  0.075 mg/kg/day

  month 1-3: 10-20 ng/mL

  month ≥4: 5-15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Prograf 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

  Prograf injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Prograf capsules. Prograf injection should be discontinued as soon as the patient can tolerate oral administration of Prograf capsules, 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 Prograf only; while monitoring Prograf concentrations in patients receiving Prograf 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 Prograf 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 Prograf 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 Prograf 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 Prograf at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

  In kidney transplant patients with post-operative oliguria, the initial dose of Prograf should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery.

  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 Prograf. Close monitoring of blood concentrations is warranted.

  The use of Prograf in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with Prograf 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 Prograf capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Prograf [see Clinical Pharmacology (12.3)].

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

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

  In patients unable to take oral Prograf capsules, therapy may be initiated with Prograf injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral Prograf 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.

  2.7 Preparation for Intravenous Product

  Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a PVC container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Due to the chemical instability of tacrolimus in alkaline media, Prograf injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).

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