Tacrolimus

Dosage Recommendations 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 or 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 capsules 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. [See table below.] Dosage should be titrated based on clinical assessments of rejection and tolerability. Tacrolimus capsules dosages lower 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 and Clinical Pharmacology ]. [See table below.] 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 or 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 ].

Dosage Recommendations for Pediatric Kidney, Liver or Heart 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 dosage 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. [See table below.] Pediatric liver transplant patients 1 0.15-0.2 mg/kg/day capsules divided in two doses, administered every 12 hours Month 1 to 12: 5 to 20 ng/mL Pediatric heart transplant patients 0.3 mg/kg/day 2 capsules or oral suspension, 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 ] . Intravenous Injection 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 information pertaining to use in adult and pediatric populations for lung transplantation is approved for Astellas Pharma US, Inc.'s Prograf® products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights (ODE-360), this drug product is not labeled with that information.

Dosage Modification for Patients with Renal Impairment Due to its potential for nephrotoxicity, consider dosing tacrolimus capsules 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 capsules 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 [see Dosage and Administration , Warnings and Precautions , Use in Specific Populations , and Clinical Pharmacology ].

Dosage Modification for 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 capsules. Close monitoring of blood concentrations is warranted. The use of tacrolimus capsules 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 , Warnings and Precautions , Use in Specific Populations , and Clinical Pharmacology ].

Important Administration Instructions Tacrolimus capsules should not be used without supervision by a physician with experience in immunosuppressive therapy. Tacrolimus capsules are 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 ] . 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 ] .

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 Formulation (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 capsules, if taken with food, it should be taken consistently the same way each time [ see ClinicalPharmacology ].

General Administration Instructions Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [ see Drug Interactions ]. 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. Therapeutic drug monitoring (TDM) is recommended for all patients receiving tacrolimus capsules [ see Dosage and Administration ].

Preparation and Administration Instructions of Tacrolimus Injection for Pharmacists Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures 1 [see How Supplied/Storage and Handling ]. Tacrolimus injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use.

Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a polyvinyl chloride (PVC) container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Due to the chemical instability of tacrolimus in alkaline media, Tacrolimus injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).

Additional information pertaining to use in adult and pediatric populations for lung transplantation is approved for Astellas Pharma US, Inc.'s Prograf® products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights (ODE-360), this drug product is not labeled with that information.