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Prophylaxis Of Organ Rejection In Kidney Transplant
ASTAGRAF XL is indicated for the prophylaxis of organ rejection in patients receiving a kidney transplant. It is recommended that ASTAGRAF XL be used concomitantly with mycophenolate mofetil (MMF) and corticosteroids, with or without basiliximab induction [see Clinical Studies]. Therapeutic drug monitoring is recommended for all patients receiving ASTAGRAF XL [see DOSAGE AND ADMINISTRATION].
Limitations Of Use
- ASTAGRAF XL extended-release capsules are not interchangeable or substitutable with tacrolimus immediate-release capsules.
- ASTAGRAF XL should not be used simultaneously with cyclosporine.
DOSAGE AND ADMINISTRATION
Dosage In Adult Kidney Transplant Recipients
Initial dosage recommendations for adult patients after kidney transplantation are presented in Table 1. Dosing of ASTAGRAF XL should be titrated based on clinical assessments of rejection and tolerability, and to maintain trough concentration ranges as noted in Table 1. Frequent monitoring of tacrolimus trough concentrations is recommended in the early post-transplant period to ensure adequate drug exposure.
ASTAGRAF XL extended-release capsules are not interchangeable or substitutible with tacrolimus immediate-release capsules.
With Basiliximab Induction
When used with basiliximab induction. MMF, and corticosteroids, the initial dose of ASTAGRAF XL should be administered prior to or within 48 hours of the completion of the transplant procedure, but may be delayed until renal function has recovered.
When used with MMF and corticosteroids, the pre-operative dose of ASTAGRAF XL should be given as one dose within 12 hours prior to reperfusion; the initial post-operative dose should be given not less than 4 hours after the pre-operative dose and within 12 hours after reperfusion.
Table 1: Recommended Initial Oral Dose and Observed
Whole Blood Trough Concentrations in Kidney Transplant Patients
|Treatment Regimen||Oral Dose||Observed Whole Blood Trough Concentrationsa|
|With basiliximab induction||0.15 mg/kg/day||Day 1 to 60: 5-17 ng/mL Month 3 to12: 4-12 ng/mL|
|Without induction||Pre-operative: 0.1 mg/kg/day Post-operative: 0.2 mg/kg/day||Day 1 to 60: 6-20 ng/mL Month 3 to 12: 6-14 ng/mL|
|a10th - 90th percentile; see also Clinical Studies for description of immunosuppressive regimens.|
African-American kidney transplant patients may require higher doses of ASTAGRAF XL to attain comparable trough concentrations compared to Caucasian patients [see CLINICAL PHARMACOLOGY, Clinical Studies].
Patients With Renal Impairment
In kidney transplant patients with post-operative oliguria, the initial dose of ASTAGRAF XL should be administered no sooner than 6 hours and within 48 hours of transplantation, but may be delayed until renal function shows evidence of recovery.
Frequent monitoring of renal function is recommended. ASTAGRAF XL dosage should be reduced if nephrotoxicity develops.
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 ASTAGRAF XL. Frequent monitoring of blood concentrations is warranted.
ASTAGRAF XL is a once daily extended-release oral formulation of tacrolimus.
Intravenous administration of tacrolimus should be reserved only for initiation in patients unable to take oral therapy. Prograf Injection is administered as a continuous IV infusion. Conversion from intravenous Prograf to oral ASTAGRAF XL is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving Prograf intravenous infusion, the first dose of oral ASTAGRAF XL therapy should be given 8-12 hours after discontinuing the Prograf IV infusion.
To ensure consistent and maximum possible drug exposure, ASTAGRAF XL capsules should be taken consistently every morning, preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal [see CLINICAL PHARMACOLOGY].
ASTAGRAF XL should be swallowed whole and should not be chewed, divided, or crushed.
Patients should not eat grapefruit or drink grapefruit juice in combination with ASTAGRAF XL [see DRUG INTERACTIONS].
Patients should not take ASTAGRAF XL with an alcoholic beverage [see DRUG INTERACTIONS].
If a dose of ASTAGRAF XL is missed, the dose may be taken up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, take by 10:00 PM). Beyond the 14-hour time frame, the patient should wait until the usual scheduled time the following morning to take the next regular daily dose. It is not recommended to double the dose of ASTAGRAF XL to make up for the missed dose.
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 the 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 or 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 the parent compound. Therefore, assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin 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.
Dosage Forms And Strengths
- 0.5 mg hard gelatin capsule with a light yellow cap and orange body branded with red “647” on the capsule body and “0.5 mg” on the capsule cap.
- 1 mg hard gelatin capsule with a white cap and orange body branded with red “677” on the capsule body and “1 mg” on the capsule cap.
- 5 mg hard gelatin capsule with a grayish-red cap and orange body branded with red “687” on the capsule body and “5 mg” on the capsule cap.
Storage And Handling
ASTAGRAF XL is supplied in short, square bottles as well as in blister cartons; the statement 'ONCE DAILY' appears on its label.
ASTAGRAF XL and tacrolimus immediate-release capsules are further differentiated by different color schemes.
ASTAGRAF XL (tacrolimus
Oblong capsule with a light yellow cap and orange body. Capsule is branded with red “647” on capsule body and “0.5 mg” on capsule cap. The capsule is supplied in 30-count short, square bottles (NDC 0469-0647-73) with brown caps and in blister cartons containing 5 blister cards of 10 capsules on each card (NDC 0469-0647-11). Both bottle and blister packaging are branded with matching brown stripes.
ASTAGRAF XL (tacrolimus
Oblong capsule with a white cap and orange body. Capsule is branded with red “677” on capsule body and “1 mg” on capsule cap. The capsule is supplied in 30-count short, square bottles (NDC 0469-0677-73) with blue caps and in blister cartons containing 5 blister cards of 10 capsules on each card (NDC 0469-0677-11). Both bottle and blister packaging are branded with matching blue stripes.
ASTAGRAF XL (tacrolimus
Oblong capsule with a grayish-red cap and orange body. Capsule is branded with red “687” on capsule body and “5 mg” on capsule cap. The capsule is supplied in 30-count short, square bottles (NDC 0469-0687-73) with orange caps and in blister cartons containing 5 blister cards of 10 capsules on each card (NDC 0469-0687-11). Both bottle and blister packaging are branded with matching orange stripes.
Store And Dispense
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].
Manufactured by: Astellas Ireland Co., Limited, Killorglin, County Kerry, Ireland. Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062. Date: February 2014.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/18/2014
Additional Astagraf XL Information
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