Tacrolimus: Package Insert and Label Information

TACROLIMUS- tacrolimus capsule
BPI LABS LLC

WARNINGS: MALIGNANCIES AND SERIOUS INFECTIONS

  • 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. 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 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 month 1-3 and 5-12 ng/mL during month 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)]

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 Tacrolimus Initial Oral DosageNote: 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 tacrolimus 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 tacrolimus 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 Adjustment 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 tacrolimus. Close monitoring of blood concentrations is warranted.

The use of tacrolimus 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 tacrolimus 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 tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [ see Clinical Pharmacology ( 12.3)].

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

Tacrolimus capsules 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.

In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus 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.

2.6 Therapeutic Drug Monitoring

Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Observed whole blood trough concentrations can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.

The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.

Methods commonly used for the assay of tacrolimus include high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer they should be deep frozen at -20° C. One study showed drug recovery >90% for samples stored at -20° C for 6 months, with reduced recovery observed after 6 months.

3 DOSAGE FORMS AND STRENGTHS

•Oblong, hard capsule for oral administration contains anhydrous tacrolimus USP as follows:

o Tacrolimus Capsules USP, 0.5 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, yellow opaque cap and yellow opaque body imprinted “ BP 665” twice on the body and imprinted “0.5 mg” twice on the cap with red ink..

o Tacrolimus Capsules USP, 1 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, white opaque cap and white opaque body imprinted “ BP 666” twice on the body and imprinted “1 mg” twice on the cap with red ink.

o Tacrolimus Capsules USP, 5 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, salmon opaque cap and salmon opaque body imprinted “ BP 667” on the body and imprinted “5 mg” twice on the cap with white ink.

4 CONTRAINDICATIONS

Tacrolimus capsules are contraindicated in patients with a hypersensitivity to tacrolimus. Tacrolimus injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions (6)].

5 WARNINGS AND PRECAUTIONS

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