Tacrolimus: Package Insert and Label Information

TACROLIMUS- tacrolimus capsule
REMEDYREPACK INC.

WARNING: MALIGNANCIES AND SERIOUS INFECTIONS

Increased risk for developing serious infections and malignancies with tacrolimus 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 adult 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)] , and pediatric patients receiving allogeneic liver transplants [see Clinical Studies (14.2)] in combination with other immunosuppressants.

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 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 capsule is 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 is 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)] .

Patients receiving tacrolimus injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen.

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, 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 [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.

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

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

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 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)].

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 to 3: 7 to 20 ng/mL

Month 4 to 12: 5 to 15 ng/mL

With MMF/IL-2 receptor antagonist

0.1 mg/kg/day, divided in two doses, administered every 12 hours

Month 1 to 12: 4 to 11 ng/mL

Liver Transplant

With corticosteroids only

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

Month 1 to 12: 5 to 20 ng/mL

Heart Transplant

With azathioprine or MMF

0.075 mg/kg/day, divided in two doses, administered every 12 hours

Month 1 to 3: 10 to 20 ng/mL

Month ≥ 4: 5 to 15 ng/mL

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 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), Clinical Pharmacology (12.3)] .

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 to 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 pertains 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)] .

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 Capsule Dosing Recommendations and Whole Blood Trough Concentration Range in Children
* 0.1 mg/kg/day if cell depleting induction treatment is administered. See Clinical Studies (14.2), Liver Transplantation.

Patient Population

Initial Tacrolimus Capsule 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.

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