Tacrolimus

TACROLIMUS- tacrolimus capsule
REMEDYREPACK INC.

WARNING: MALIGNANCIES AND SERIOUS INFECTIONS

  • Increased risk for developing serious infections and malignancies with tacrolimus capsules or other immunosuppressants that may lead to hospitalization or death. (5.1, 5.2)

1 INDICATIONS AND USAGE

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

Tacrolimus capsules are 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 General Instructions

Tacrolimus capsules are not interchangeable or substitutable with 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 [see Warnings and Precautions (5.3)].

Tacrolimus capsules should not be used without supervision of a physician with experience in immunosuppressive therapy.

Oral Formulations (Capsules and Oral Suspension)

If patients are able to initiate therapy, the recommended starting doses should be initiated. Advise patients not to eat grapefruit or drink grapefruit juice while under treatment with tacrolimus [see Drug Interactions (7.2)].

Therapeutic drug monitoring is recommended for all patients receiving tacrolimus [see Dosage and Administration (2.7)].

2.2 Administration

Tacrolimus capsules may be taken with or without food. However, since the presence of food affects the bioavailability of tacrolimus, if taken with food, it should be taken consistently the same way each time [see Clinical Pharmacology (12.3)].

Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus [see Drug Interactions (7.2)]. Tacrolimus should not be used simultaneously with cyclosporine. Tacrolimus or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

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

Capsules

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 capsule 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

* 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 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during month 1 to 3 and 5 to 12 ng/mL during month 4 to 12 [see Clinical Studies (14.1)].

Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsule 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 Clinical Pharmacology (12.3)]

Patient Population Tacrolimus Capsules* Initial Oral Dosing 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

Table 2. Comparative Dose and Trough Concentrations Based on Race

Time After Transplant Caucasian n=114 African-American 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 to 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 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)].

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