Prescription Drug Information: Tacrolimus

TACROLIMUS- tacrolimus capsule
Aphena Pharma Solutions — Tennessee, LLC

WARNING: MALIGNANCIES AND SERIOUS INFECTIONSBOXED WARNING – MALIGNANCIES AND SERIOUS INFECTIONS

Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression (5.2)
Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections (5.3, 5.4, 5.5)
Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus capsules (5.1)
Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression [see Warnings and Precautions (5.2)].
Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Warnings and Precautions (5.3, 5.4, 5.5)].
Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Organ Rejection in Kidney Transplant

Tacrolimus capsules, USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that tacrolimus capsules 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 capsules [see Dosage and Administration (2.6)].

1.2 Prophylaxis of Organ Rejection in Liver Transplant

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

1.3 Prophylaxis of Organ Rejection in Heart Transplant

Tacrolimus capsules are 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)].

Tacrolimus injection should be reserved for patients unable to take tacrolimus capsules orally [see Warnings and Precautions (5.11)].

Use with sirolimus is not recommended in liver and heart transplant. The safety and efficacy of tacrolimus capsules 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 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. 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 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

Recommended Tacrolimus Capsules 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 to 3: 7 to 20 ng/mL

month 4 to 12: 5 to 15 ng/mL

In combination with MMF/IL-2 receptor antagonist *

0.1 mg/kg/day

month 1 to 12: 4 to 11 ng/mL

Adult liver transplant patients

0.10 to 0.15 mg/kg/day

month 1 to 12: 5 to 20 ng/mL

Adult heart transplant patients

0.075 mg/kg/day

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 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

0.23

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

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus 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 to 0.05 mg/kg/day.

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

Patient Population

Recommended Tacrolimus Capsules 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 to 0.20 mg/kg/day

Month 1 to 12: 5 to 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.

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