Tacrolimus (Page 2 of 16)

2.3 Dosing for Pediatric Kidney, Liver, and Heart 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

Patient Population	Initial Tacrolimus Capsules USP	Whole Blood Trough Concentration Range
Pediatric kidney transplant patients †	0.3 mg/kg/day capsules, divided in two doses, administered every 12 hours	Month 1-12: 5-20 ng/mL
Pediatric liver transplant patients ‡	0.15- 0.2 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-12: 5-20 ng/ mL
Pediatric heart transplant patients †	0.3 mg/kg/day* capsules, divided in two doses, administered every 12 hours	Month 1-12: 5-20 ng/mL

*0.1 mg/kg/day if cell depleting induction treatment is administered

† See Clinical Pharmacology ( 12.3) , Tacrolimus Granules Pharmacokinetics in Pediatric Patients
‡ See Clinical Studies ( 14.2) , Liver Transplantation

For conversion of pediatric patients from tacrolimus granules to tacrolimus capsules or from tacrolimus capsules to tacrolimus granules, 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 0.03-0.05 mg/kg/day.

2.4 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 [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 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 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.

3 DOSAGE FORMS AND STRENGTHS

Tacrolimus Capsules, USP are available in the following dosage form and strengths: Oblong shape, hard gelatin capsules for oral administration contains tacrolimus as follows:

• Tacrolimus Capsules, USP, 0.5 mg: Light yellow color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “0.5” in red ink on body and cap respectively.
• Tacrolimus Capsules, USP, 1 mg: White color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “1.0” in red ink on body and cap respectively.
• Tacrolimus Capsules, USP, 5 mg: Pink color, oblong shape, size “4” hard gelatin capsules printed with “PBT” and “5.0” in red ink on body and cap respectively.

4 CONTRAINDICATIONS

Tacrolimus capsules are contraindicated in patients with a hypersensitivity to tacrolimus. Tacrolimus injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions ( 6)] .

5 WARNINGS AND PRECAUTIONS

5.1 Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including Tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin [ see Boxed Warning]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, examine patients for skin changese; xposure to sunlight and UV light should be limited by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor.

Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment.