Tacrolimus: Package Insert and Label Information

TACROLIMUS- tacrolimus capsule, gelatin coated
Panacea Biotec Limited

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Organ Rejection in Kidney, Liver, and Heart Transplant

Tacrolimus Capsules is indicated for the prophylaxis of organ rejection, in patients receiving allogeneic kidney transplant [see Clinical Studies ( 14.1)] , liver transplants [see Clinical Studies ( 14.2)] and heart transplant [see Clinical Studies ( 14.3)] , in combination with other immunosuppressants.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

Tacrolimus Capsules should not be used without supervision by a physician with experience in immunosuppressive therapy.

Tacrolimus capsules and tacrolimus granules are not interchangeable or substitutable for other tacrolimus extended-release products. This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product. Under-or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision [see Warnings and Precautions ( 5.3)]. Intravenous Formulation -Administration Precautions due to Risk of Anaphylaxis

Intravenous use is recommended for patients who cannot tolerate oral formulations, and conversion from intravenous to oral tacrolimus capsules are recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions that occurred with injectables containing castor oil derivatives [see Warnings and Precautions ( 5.9)].

Oral Formulations (Capsules)

If patients are able to initiate oral therapy, the recommended starting doses should be initiated. Tacrolimus capsules may be taken with or without food. However, since the presence of food affects the bioavailability of tacrolimus capsules, if taken with food, it should be taken consistently the same way each time [see Clinical Pharmacology ( 12.3)].

General Administration Instructions

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

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

Therapeutic drug monitoring (TDM) is recommended for all patients receiving tacrolimus capsules [see Dosage and Administration ( 2.6)].

2.2 Dosing for Adult Kidney, Liver, or Heart Transplant Patients — Capsules

Capsules

If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated. The initial dose of tacrolimus capsules 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 tacrolimus capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered.

The initial oral tacrolimus dosage recommendations for adult patients with kidney, liver, or heart transplants and whole blood trough concentration range are shown in Table 1. Perform therapeutic drug monitoring (TDM) to ensure that patients are within the ranges listed in Table 1.

Table 1. Summary of Initial Oral Tacrolimus capsules Dosing Recommendations and Whole Blood Trough Concentration Range in Adults

Patient Population	Tacrolimus Capsules* Initial Oral Dosage	Whole Blood Trough Concentration Range
kidney Transplant
With azathioprine	0.2 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL
With MMF/IL-2 receptor antagonist†	0.1 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-12: 4-11 ng/mL
Liver Transplant
With corticosteroids only	0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-12: 5-20 ng/mL
Heart Transplant
With azathioprine or MMF	0.075 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL

*African-American patients may require higher doses compared to Caucasians (see Table 2)

† 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)].

Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsules 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 African-American patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients ( Table 2) [see Use in Specific Populations ( 8.8) and Clinical Pharmacology ( 12.3)].

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

Intravenous Injection

Tacrolimus injection should be used only as a continuous intravenous infusion and should be discontinued as soon as the patient can tolerate oral administration. The first dose of tacrolimus capsules should be given 8-12 hours after discontinuing the intravenous infusion.

The recommended starting dose of tacrolimus 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 intravenous infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

The whole blood trough concentration range described in Table 1 pertain to oral administration of tacrolimus capsules only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous intravenous 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.

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as Tacrolimus injection. Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions ( 5.9)].

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.