Tacrolimus

TACROLIMUS- tacrolimus capsule
Belcher Pharmaceuticals,LLC

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Organ Rejection in Kidney Transplant

Tacrolimus Capsules is indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that tacrolimus be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies ( 14.1)] . Therapeutic drug monitoring is recommended for all patients receiving tacrolimus [see Dosage and Administration ( 2.6)].

1.2 Prophylaxis of Organ Rejection in Liver Transplant

Tacrolimus Capsules is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that tacrolimus be used concomitantly with adrenal corticosteroids [see Clinical Studies ( 14.2)] . Therapeutic drug monitoring is recommended for all patients receiving tacrolimus [see Dosage and Administration ( 2.6)].

1.3 Prophylaxis of Organ Rejection in Heart Transplant

Tacrolimus Capsules is indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that tacrolimus capsules be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies ( 14.3)] . Therapeutic drug monitoring is recommended for all patients receiving tacrolimus capsules [see Dosage and Administration ( 2.6)].

1.4 Limitations of Use

Tacrolimus Capsules should not be used simultaneously with cyclosporine [see Dosage and Administration ( 2.5)].

Use with sirolimus is not recommended in liver and heart transplant. The safety and efficacy of tacrolimus with sirolimus has not been established in kidney transplant [see Warnings and Precautions ( 5.12)].

Intravenous use reserved for patients who cannot tolerate capsules orally.

2 DOSAGE AND ADMINISTRATION

2.1 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 tacrolimus 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 may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see Dosage and Administration ( 2.6 )

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

Patient Population	Recommended Tacrolimus 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		month 1-3: 7-20 ng/mL
In combination with azathioprine	0.2 mg/kg/day	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

^a) 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 months 1-3 and 5-12 ng/mL during months 4-12 [see Clinical Studies ( 14.1)].

Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus 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

Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus, 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 tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus 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 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 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 Tacrolimus injection [ see Warnings and Precautions ( 5.11) ]