Tacrolimus intravenous
Other products: Tacrolimus, Tacrolimus extended-release
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Boxed warning
WARNING: MALIGNANCIES and SERIOUS INFECTIONS Increased risk for developing serious infections and malignancies with Tacrolimus Injection or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 ) WARNING: MALIGNANCIES and SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Increased risk for developing serious infections and malignancies with Tacrolimus Injection or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 )
Handling and access
NIOSH hazardous drug
Table 2NIOSH lists tacrolimus as a hazardous drug. AHFS class: 84:92 skin and mucous membrane agents, miscellaneous; 92:44 immunosuppressive agents.
- Meets the NIOSH definition of a hazardous drug (carcinogenicity, developmental or reproductive toxicity, organ toxicity at low doses, or genotoxicity) without MSHI or a Group 1 or 2A carcinogen classification.
Handle with the precautions your facility uses for hazardous drugs (USP <800>). NIOSH's Managing Hazardous Drug Exposures lists controls by drug form and activity.
Dosing in kidney impairment
Dosage Recommendations for Adult Kidney, Liver, or Heart Transplant Patients - Injection 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 Prograf® capsules should be given 8-12 hours after discontinuing the intravenous infusion.
The recommended starting dose of Tacrolimus injection is 0.03-0.05 mg/kg/day in kidney or liver transplant, 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.
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 Modification for Patients with Renal Impairment Due to its potential for nephrotoxicity, consider dosing tacrolimus injection 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 [see Dosage and Administration, Warnings and Precautions, Use in Specific Populations, and Clinical Pharmacology] .
Dosing in liver impairment
Dosage Recommendations for Pediatric Liver Transplant Patients 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 0.03–0.05 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.
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. 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, Warnings and Precautions, Use in Specific Populations, and Clinical Pharmacology].
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Preparation and administration
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Important Administration Instructions Tacrolimus should not be used without supervision by a physician with experience in immunosuppressive therapy. 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.
General Administration Instructions Patients should not eat grapefruit or drink grapefruit juice in combination with Tacrolimus [see Drug Interactions]. 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].
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).
Drug interactions
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- Tacrolimus intravenous
Label text (10 paragraphs)
Mycophenolic Acid Products: Can increase MPA exposure after crossover from cyclosporine to tacrolimus; monitor for MPA-related adverse reactions and adjust MMF or MPA dose as needed. ( 7.1 ) Nelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use. ( 7.2 ) CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. ( 5.11 , 7.2 ) CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. ( 5.11 , 7.2 )
7.1 Mycophenolic Acid When tacrolimus is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with tacrolimus co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.
7.2 Effects of Other Drugs on Tacrolimus Table 15 displays the effects of other drugs on Tacrolimus. Table 15: Effects of Other Drugs/Substances on Tacrolimus 1 1. Tacrolimus dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology ( 12.3 )] , literature reports of altered tacrolimus exposures, or the other drug's known CYP3A inhibitor/inducer status. 2. High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate 3.
CYP3A inhibitor.Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate). Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juice 2 May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )] . Avoid grapefruit or grapefruit juice.
Strong CYP3A Inducers 3 : Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John's Wort May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions ( 5.11 )] . Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )] .
Strong CYP3A Inhibitors 3 : Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )] .
Reduce tacrolimus dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )] . Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary [see Warnings and Precautions ( 5.11 )].
Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )] . Monitor tacrolimus whole blood trough concentrations and reduce Tacrolimus dose if needed [see Dosage and Administration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )] .
Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )] . Monitor tacrolimus whole blood trough concentrations and reduce Tacrolimus dose if needed [see Dosage and Administration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )] . Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone May decrease tacrolimus whole blood trough concentrations.
Monitor tacrolimus whole blood trough concentrations and adjust Tacrolimus dose if needed [see Dosage and Administration ( 2.2 , 2.6 )] . Caspofungin May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see Dosage and Administration ( 2.2 , 2.6 )] . Direct Acting Antiviral (DAA) Therapy The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of tacrolimus is warranted to ensure continued efficacy and safety [see Dosage and Administration ( 2.2 , 2.6 )] .
Contraindications
Tacrolimus injection is 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 )] . Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
CLikelihood score C: Probable rare cause of clinically apparent liver injury.
Tacrolimus is a calcineurin inhibitor and potent immunosuppressive agent used largely as a means of prophylaxis against cellular rejection after transplantation. Tacrolimus therapy can be associated with mild serum enzyme elevations, and it has been linked to rare instances of clinically apparent cholestatic liver injury.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to Tacrolimus during pregnancy. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus. Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org / .
Risk Summary Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress [see Human Data ]. Advise pregnant women of the potential risk to the fetus.
Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses (0.5 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis).
Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data ]. The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following…
Breastfeeding (LactMed)
The amounts of systemically administered tacrolimus are low in breastmilk and do not adversely affect the breastfed infant. Tacrolimus has been used extensively by nursing mothers and United States and European expert guidelines consider tacrolimus to be acceptable during breastfeeding. Exclusively breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern. Topical tacrolimus presents a low risk to the nursing infant because it is poorly absorbed after topical application and peak blood concentrations are less than 2 mcg/L in most patients. Ensure that the infant’s skin does not come into direct contact with the areas of skin that have been treated.
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