Prograf: Package Insert and Label Information

PROGRAF- tacrolimus capsule, gelatin coated
Aphena Pharma Solutions — Tennessee, LLC

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Organ Rejection in Kidney Transplant

Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that Prograf 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 Prograf [see Dosage and Administration (2.6)].

1.2 Prophylaxis of Organ Rejection in Liver Transplant

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

1.3 Prophylaxis of Organ Rejection in Heart Transplant

Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that Prograf 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 Prograf [see Dosage and Administration (2.6)].

1.4 Limitations of Use

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

Prograf injection should be reserved for patients unable to take Prograf capsules orally [see Dosage and Administration (2.1) and Warnings and Precautions (5.11)].

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

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 Prograf 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 Prograf 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

* 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)].
Patient Population	Recommended Prograf 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
In combination with azathioprine	0.2 mg/kg/day	month 1-3: 7-20 ng/mL month 4-12: 5-15 ng/mL
In combination with MMF/IL-2 receptor antagonist *	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

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

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

2.2 Dosage in Pediatric Liver Transplant Patients

The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration (2.6). If necessary, pediatric patients may start on an IV dose of 0.03-0.05 mg/kg/day.

Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children

Patient Population	Recommended Prograf Initial Oral Dosage Note: daily doses should be administered as two divided doses, every 12 hours	Observed Tacrolimus Whole Blood Trough Concentrations
Pediatric liver transplant patients	0.15-0.20 mg/kg/day	Month 1-12: 5-20 ng/mL

Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

Experience in pediatric kidney and heart transplantation patients is limited.

2.3 Dosage Adjustment in Patients with Renal Impairment

Due to its potential for nephrotoxicity, consideration should be given to dosing Prograf 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 Prograf 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.

2.4 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 Prograf. Close monitoring of blood concentrations is warranted.

The use of Prograf 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 (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.5 Administration Instructions

It is recommended that patients initiate oral therapy with Prograf capsules if possible.

Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3[see Dosage and Administration (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration (2.1)].

It is important to take Prograf capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Prograf [see Clinical Pharmacology (12.3)].

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

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

In patients unable to take oral Prograf capsules, therapy may be initiated with Prograf injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion.