Tacrolimus (Page 2 of 11)

2.3 Dosing for Pediatric Liver Transplant Patients

Oral formulation (capsules)

Pediatric patients in general need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosing for pediatric transplant patients and whole blood trough concentration range are shown in Table 3. Perform TDM to ensure that patients are within the ranges listed in Table 3.

Table 3. Summary of Initial Tacrolimus Capsules Dosing Recommendations and Whole Blood Trough Concentration Range in Children

*
See Clinical Studies (14.2), Liver Transplantation

Patient Population

Initial Tacrolimus Capsules Dosing

Whole Blood Trough Concentration Range

Pediatric liver transplant patients *

0.15 to 0.2 mg/kg/day capsules divided in two doses, administered every 12 hours

Month 1 to 12: 5 to 20 ng/mL

For conversion of pediatric patients from tacrolimus for oral suspension to Tacrolimus capsules or from Tacrolimus capsules to tacrolimus for oral suspension, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration (2.6)]. If a patient is unable to receive an oral formulation, the patient may be started on tacrolimus injection. For pediatric liver transplant patients, the intravenous dose is 0.03 to 0.05 mg/kg/day.

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.4 Dosage Adjustment in Patients with Renal Impairment

Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

In kidney transplant patients with post-operative oliguria, the initial dose of tacrolimus should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration (2.2) , Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

2.5 Dosage Adjustment 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 in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

2.6 Therapeutic Drug Monitoring

Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments, and compliance. Whole blood trough concentration range can be found in Table 1.

Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.

The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.

Methods commonly used for the assay of tacrolimus include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore, assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) 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 and Administration Instructions of Tacrolimus Injection for Pharmacists

Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures1 [see How Supplied/Storage and Handling (16.4)]..

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

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

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

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

3 DOSAGE FORMS AND STRENGTHS

Tacrolimus Capsules, USP are available in the following strengths:

Capsules

Hard gelatin capsules for oral administration contains anhydrous tacrolimus USP as follows:

• 0.5 mg, light-yellow color, imprinted in red “ Biocon Logo” on the capsule cap and “ T 0.5” on capsule body

• 1 mg, white color, imprinted in red “Biocon logo” on the capsule cap and “ T 1” on capsule body

• 5 mg, greyish-red color, imprinted with white “Biocon logo” on the capsule cap and “ T 5” on capsule body

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