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Prograf

"Analysis of three biomarkers in the urine of kidney transplant recipients can diagnose — and even predict — transplant rejection, according to results from a clinical trial sponsored by the National Institute of Allergy and Infect"...

Prograf

INDICATIONS

Prophylaxis of Organ Rejection in Kidney Transplant

Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that Prograf be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies]. Therapeutic drug monitoring is recommended for all patients receiving Prograf [see DOSAGE AND ADMINISTRATION].

Prophylaxis of Organ Rejection in Liver Transplant

Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that Prograf be used concomitantly with adrenal corticosteroids [see Clinical Studies]. Therapeutic drug monitoring is recommended for all patients receiving Prograf [see DOSAGE AND ADMINISTRATION].

Prophylaxis of Organ Rejection in Heart Transplant

Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that Prograf be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies]. Therapeutic drug monitoring is recommended for all patients receiving Prograf [see DOSAGE AND ADMINISTRATION].

Limitations of Use

Prograf should not be used simultaneously with cyclosporine [see DOSAGE AND ADMINISTRATION].

Prograf injection should be reserved for patients unable to take Prograf capsules orally [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Use with sirolimus is not recommended in liver and heart transplant. The safety and efficacy of Prograf with sirolimus has not been established in kidney transplant [see WARNINGS AND PRECAUTIONS].

DOSAGE AND ADMINISTRATION

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 Therapeutic Drug Monitoring below.

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

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 a 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
aIn 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].

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].

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 below. 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.

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.

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 Use In Specific Populations and CLINICAL PHARMACOLOGY].

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. for blood concentration monitoring details in kidney transplant patients.

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].

Patients should not eat grapefruit or drink grapefruit juice in combination with Prograf [see DRUG INTERACTIONS].

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.

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.

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).

HOW SUPPLIED

Dosage Forms And Strengths

  • Oblong, hard capsule for oral administration contains anhydrous tacrolimus USP as follows:
    • 0.5 mg, light-yellow color, imprinted in red “0.5 mg” on the capsule cap and “logo607”* on capsule body
    • 1 mg, white color, imprinted in red “1 mg” on the capsule cap and “logo617”* on capsule body
    • 5 mg, grayish-red color, imprinted with white “5 mg” on the capsule cap and “logo657”* on capsule body *The logo is a letter 'f' in a box as shown on the capsules --f
  • 1 mL ampule for IV infusion contains anhydrous tacrolimus USP as follows:
    • 5 mg/mL, sterile solution

Storage And Handling

Prograf (tacrolimus) Capsules USP

strength 0.5 mg (containing the equivalent of 0.5 mg anhydrous tacrolimus USP) 1 mg (containing the equivalent of 1 mg anhydrous tacrolimus USP) 5 mg (containing the equivalent of 5 mg anhydrous tacrolimus USP)
shape/color oblong/light yellow oblong/white oblong/grayish red
branding on capsule cap/body f607 f 617 f657
100 count bottle NDC 0469-0607-73 NDC 0469-0617-73 NDC 0469-0657-73
10 blister cards of 10 capsules -- NDC 0469-0617-11 NDC 0469-0657-11

Note: Prograf capsules USP are not filled to maximum capsule capacity. Capsule contains labeled amount.

Store and Dispense

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).

Prograf (tacrolimus) Injection

(for IV infusion only)

NDC 0469-3016-01 Product Code 301601

5 mg/mL (equivalent of 5 mg of anhydrous tacrolimus USP per mL) supplied as a sterile solution in a 1 mL ampule, in boxes of 10 ampules

Store and Dispense

Store between 5°C and 25°C (41°F and 77°F).

Ampules manufactured by: Astellas Ireland Co., Limited, Killorglin, County Kerry, Ireland. Capsules manufactured by: Astellas Pharma Tech, Co., Ltd., Toyama Technology Center 2-178 Kojin-machi, Toyama city, Toyama 930-0809, Japan. Marketed by: Astellas Pharma US, Inc. Northbrook, IL 60062. Revised: August 2013.

Last reviewed on RxList: 9/23/2013
This monograph has been modified to include the generic and brand name in many instances.

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