Tacrolimus - Tacrolimus capsule Prescribing Information
- Increased risk for developing serious infections and malignancies with Tacrolimus or other immunosuppressants that may lead to hospitalization or death. (
5.1 Lymphoma and Other MalignanciesPatients receiving immunosuppressants, including tacrolimus, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [
see Boxed Warning]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.As usual for patients with increased risk for skin cancer,examine patients for skin changes; exposure to sunlight and UV light should be limited by wearing protective clothing and using a board-spectrum sunscreen with a high protection factor.
Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein-Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment.
,5.2 Serious InfectionsPatients receiving immunosuppressants, including tacrolimus, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:
• Polyomavirus-associated nephropathy (PVAN), mostly due to BK virus infection
• JC virus-associated progressive multifocal leukoencephalopathy (PML)
• Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing CMV viremia and CMV disease.
Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [
see Adverse Reactions(6.1,6.2)].)
Tacrolimus capsules are calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult patients receiving allogeneic liver, kidney or heart transplants and pediatric patients receiving allogeneic liver transplants in combination with other immunosuppressants. (
Tacrolimus capsules are indicated for the prophylaxis of organ rejection, in adult patients receiving allogeneic kidney transplant [
| Patient Population | Initial Oral Dosage | Whole Blood Trough Concentration Range |
ADULT | ||
| Kidney Transplant | ||
| With azathioprine | 0.2 mg/kg/day capsules, divided in two doses, every 12 hours | Month 1 to 3: 7 to 20 ng/mL Month 4 to 12: 5 to 15 ng/mL |
| With MMF/IL-2 receptor antagonist | 0.1 mg/kg/day capsules, divided in two doses, every 12 hours | Month 1 to 12: 4 to 11 ng/mL |
| Liver Transplant | ||
| With corticosteroids only | 0.1 to 0.15 mg/kg/day capsules, divided in two doses, every 12 hours | Month 1 to 12: 5 to 20 ng/mL |
| Heart Transplant | ||
| With azathioprine or MMFMMF= Mycophenolate mofetil | 0.075 mg/kg/day capsules, divided in two doses, every 12 hours | Month 1 to 3: 10 to 20 ng/mL Month ≥ 4: 5 to 15 ng/mL |
PEDIATRIC | ||
| Liver Transplant | ||
| 0.15 to 0.2 mg/kg/day capsules divided in two doses, every 12 hours | Month 1 to 12: 5 to 20 ng/mL | |
• Intravenous (IV) use recommended for patients who cannot tolerate oral formulations (capsules). (
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
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 (5.9)].
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.
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, if taken with food, it should be taken consistently the same way each time
Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules
Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules 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
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 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.
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.
Patient Population | Tacrolimus CapsulesAfrican-American patients may require higher doses compared to Caucasians (see Table 2)Initial Oral Dosing | Whole Blood Trough Concentration Range |
| Kidney Transplant | ||
| With Azathioprine | 0.2 mg/kg/day, divided in two doses, administered every 12 hours | Month 1 to 3: 7 to 20 ng/mL Month 4 to 12: 5 to 15 ng/mL |
| With MMF/IL-2 receptor antagonistIn 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) ] | 0.1 mg/kg/day, divided in two doses, administered every 12 hours | Month 1 to 12: 4 to 11 ng/mL |
| Liver Transplant | ||
| With corticosteroids only | 0.10 to 0.15 mg/kg/day, divided in two doses, administered every 12 hours | Month 1 to 12: 5 to 20 ng/mL |
| Heart Transplant | ||
| With azathioprine or MMF | 0.075 mg/kg/day, divided in two doses, administered every 12 hours | 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 capsules 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 African-American patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2)
Time After Transplant | Caucasian | African-American | ||
| N = 114 | 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 |
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 and 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 [
• Administer capsules consistently with or without food. (
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
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 (5.9)].
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.
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, if taken with food, it should be taken consistently the same way each time
Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules
Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules 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
• Therapeutic drug monitoring is recommended. (
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
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 (5.9)].
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.
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, if taken with food, it should be taken consistently the same way each time
Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules
Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules 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
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. Whole blood trough concentration range 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.
• Avoid eating grapefruit or drinking grapefruit juice. (
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
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 (5.9)].
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.
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, if taken with food, it should be taken consistently the same way each time
Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules
Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules 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 dosing adjustments for African-American patients (
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 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.
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.
Patient Population | Tacrolimus CapsulesAfrican-American patients may require higher doses compared to Caucasians (see Table 2)Initial Oral Dosing | Whole Blood Trough Concentration Range |
| Kidney Transplant | ||
| With Azathioprine | 0.2 mg/kg/day, divided in two doses, administered every 12 hours | Month 1 to 3: 7 to 20 ng/mL Month 4 to 12: 5 to 15 ng/mL |
| With MMF/IL-2 receptor antagonistIn 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) ] | 0.1 mg/kg/day, divided in two doses, administered every 12 hours | Month 1 to 12: 4 to 11 ng/mL |
| Liver Transplant | ||
| With corticosteroids only | 0.10 to 0.15 mg/kg/day, divided in two doses, administered every 12 hours | Month 1 to 12: 5 to 20 ng/mL |
| Heart Transplant | ||
| With azathioprine or MMF | 0.075 mg/kg/day, divided in two doses, administered every 12 hours | 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 capsules 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 African-American patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2)
Time After Transplant | Caucasian | African-American | ||
| N = 114 | 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 |
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 and 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 [
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 [
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 [
• For complete dosing information, see the full prescribing information
Tacrolimus Capsules, USP are available in the following strengths:
| Capsules | Hard gelatin capsules for oral administration contains anhydrous tacrolimus USP as follows: • 0.5 mg, light-yellow color, imprinted in red “ Biocon Logo" on the capsule cap and “ T 0.5” on capsule body • 1 mg, white color, imprinted in red “Biocon logo” on the capsule cap and “ T 1” on capsule body • 5 mg, greyish-red color, imprinted with white "Biocon logo” on the capsule cap and “ T 5” on capsule body |
- Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. (,
8.1 PregnancyRisk SummaryTacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus
in uteroare 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/m2basis). 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/m2basis). 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/m2basis). 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 ConsiderationsDisease-Associated Maternal and/or Embryo-Fetal RiskRisks during pregnancy are increased in organ transplant recipients.
The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death.
Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported.
Maternal Adverse ReactionsTacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [
see Warnings and Precautions (5.4)].Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [
see Warnings and Precautions].Fetal/Neonatal Adverse ReactionsRenal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking tacrolimus.
Labor or DeliveryThere is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus.
DataHuman DataThere are no adequate and well controlled studies on the effects of tacrolimus in human pregnancy. Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus in utero have an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress.
TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 16. In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for renal and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.
Table 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to TacrolimusKidney Liver Pregnancy OutcomesIncludes multiple births and terminations.462 253 Miscarriage24.5% 25% Live births331180Pre-term delivery (< 37 weeks) 49% 42% Low birth weight (< 2500 g) 42% 30% Birth defects 8%Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. 5% Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients, and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients.
Animal DataAdministration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m2basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (2.6 to 6.9 times the recommended clinical dose range) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.
In a peri-/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects on parturition, and reduced pup viability at 3.2 mg/kg (2.6 to 6.9 times the recommended clinical dose range); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1.0 mg/kg (0.8 to 2.2 times the recommended clinical dose range).
Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation, produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (2.6 to 6.9 times the recommended clinical dose range). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 to 2.2 times the recommended clinical dose range) [
see Nonclinical Toxicology (13.1)].)8.3 Females and Males of Reproductive PotentialContraceptionTacrolimus can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment with tacrolimus
[see Use in Specific Populations (8.1)and Nonclinical Toxicology (13.1)].InfertilityBased on findings in animals, male and female fertility may be compromised by treatment with tacrolimus
[see Nonclinical Toxicology (13.1)].
| 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 |
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 [
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
• Lymphoma and Other Malignancies [
• Serious Infections [
• New Onset Diabetes After Transplant [
• Nephrotoxicity [
• Neurotoxicity [
• Hyperkalemia [
• Hypertension [
• Anaphylactic Reactions with Tacrolimus Injection [
• Myocardial Hypertrophy [
• Pure Red Cell Aplasia [
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.
The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.
Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in trial where 205 patients received tacrolimus based immunosuppression and 207 patients received cyclosporine based immunosuppression. The trial population had a mean age of 43 years (mean±sd was 43±13 years on tacrolimus and 44±12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%) and Other (5%). The 12 month post-transplant information from this trial is presented below.
The most common adverse reactions ( ≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.
Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:
Tacrolimus/AZA (N=205) | Cyclosporine/AZA (N=207) | |
Nervous System | ||
Tremor Headache Insomnia Paresthesia Dizziness | 54% 44% 32% 23% 19% | 34% 38% 30% 16% 16% |
Gastrointestinal | ||
Diarrhea Nausea Constipation Vomiting Dyspepsia | 44% 38% 35% 29% 28% | 41% 36% 43% 23% 20% |
Cardiovascular | ||
Hypertension Chest Pain | 50% 19% | 52% 13% |
Urogenital | ||
Creatinine Increased Urinary Tract Infection | 45% 34% | 42% 35% |
Metabolic and Nutritional | ||
Hypophosphatemia Hypomagnesemia Hyperlipemia Hyperkalemia Diabetes Mellitus Hypokalemia Hyperglycemia Edema | 49% 34% 31% 31% 24% 22% 22% 18% | 53% 17% 38% 32% 9% 25% 16% 19% |
Hemic and Lymphatic | ||
Anemia Leukopenia | 30% 15% | 24% 17% |
Miscellaneous | ||
Infection Peripheral Edema Asthenia Abdominal Pain Pain Fever Back Pain | 45% 36% 34% 33% 32% 29% 24% | 49% 48% 30% 31% 30% 29% 20% |
Respiratory System | ||
Dyspnea Cough Increased | 22% 18% | 18% 15% |
Musculoskeletal | ||
Arthralgia | 25% | 24% |
Skin | ||
Rash Pruritus | 17% 15% | 12% 7% |
Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n=403), or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12 month post-transplant information from this trial is presented below.
Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:
| Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C= Tac/MMF/CS/Daclizumab. CsA= Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil. | ||||||
Tacrolimus (Group C) | Cyclosporine (Group A) | Cyclosporine (Group B) | ||||
(N=403) | (N=384) | (N=408) | ||||
Diarrhea | 25% | 16% | 13% | |||
Urinary Tract Infection | 24% | 28% | 24% | |||
Anemia | 17% | 19% | 17% | |||
Hypertension | 13% | 14% | 12% | |||
Leukopenia | 13% | 10% | 10% | |||
Edema Peripheral | 11% | 12% | 13% | |||
Hyperlipidemia | 10% | 15% | 13% | |||
In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received
Adverse reactions that occurred in ≥15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below:
Tacrolimus/MMF | Cyclosporine/MMF | |
(N=212) | (N=212) | |
Gastrointestinal Disorders | ||
Diarrhea | 44% | 26% |
Nausea | 39% | 47% |
Constipation | 36% | 41% |
Vomiting | 26% | 25% |
Dyspepsia | 18% | 15% |
Injury, Poisoning, and Procedural Complications | ||
Post-Procedural Pain | 29% | 27% |
Incision Site Complication | 28% | 23% |
Graft Dysfunction | 24% | 18% |
Metabolism and Nutrition Disorders | ||
Hypomagnesemia | 28% | 22% |
Hypophosphatemia | 28% | 21% |
Hyperkalemia | 26% | 19% |
Hyperglycemia | 21% | 15% |
Hyperlipidemia | 18% | 25% |
Hypokalemia | 16% | 18% |
Nervous System Disorders | ||
Tremor | 34% | 20% |
Headache | 24% | 25% |
Blood and Lymphatic System Disorders | ||
Anemia | 30% | 28% |
Leukopenia | 16% | 12% |
Miscellaneous | ||
Edema Peripheral | 35% | 46% |
Hypertension | 32% | 35% |
Insomnia | 30% | 21% |
Urinary Tract Infection | 26% | 22% |
Blood Creatinine Increased | 23% | 23% |
Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection
There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to70); the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%) and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%) and Other (2%).
The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation.
The most common adverse reactions (≥ 38%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral administration of tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials.
U.S. TRIAL | EUROPEAN TRIAL | |||
Tacrolimus (N=250) | Cyclosporine/AZA (N=250) | Tacrolimus (N=264) | Cyclosporine/AZA (N=265) | |
Nervous System | ||||
Headache Insomnia Tremor Paresthesia | 64% 64% 56% 40% | 60% 68% 46% 30% | 37% 32% 48% 17% | 26% 23% 32% 17% |
Gastrointestinal | ||||
Diarrhea Nausea LFT Abnormal Anorexia Vomiting Constipation | 72% 46% 36% 34% 27% 24% | 47% 37% 30% 24% 15% 27% | 37% 32% 6% 7% 14% 23% | 27% 27% 5% 5% 11% 21% |
Cardiovascular | ||||
Hypertension | 47% | 56% | 38% | 43% |
Urogenital | ||||
Kidney Function Abnormal | 40% | 27% | 36% | 23% |
Creatinine Increased | 39% | 25% | 24% | 19% |
BUN Increased | 30% | 22% | 12% | 9% |
Oliguria | 18% | 15% | 19% | 12% |
Urinary Tract Infection | 16% | 18% | 21% | 19% |
Metabolic and Nutritional | ||||
Hypomagnesemia Hyperglycemia Hyperkalemia Hypokalemia | 48% 47% 45% 29% | 45% 38% 26% 34% | 16% 33% 13% 13% | 9% 22% 9% 16% |
Hemic and Lymphatic | ||||
Anemia Leukocytosis Thrombocytopenia | 47% 32% 24% | 38% 26% 20% | 5% 8% 14% | 1% 8% 19% |
Miscellaneous | ||||
Pain Abdominal Pain Asthenia Fever Back Pain Ascites Peripheral Edema | 63% 59% 52% 48% 30% 27% 26% | 57% 54% 48% 56% 29% 22% 26% | 24% 29% 11% 19% 17% 7% 12% | 22% 22% 7% 22% 17% 8% 14% |
Respiratory System | ||||
Pleural Effusion Dyspnea Atelectasis | 30% 29% 28% | 32% 23% 30% | 36% 5% 5% | 35% 4% 4% |
Skin and Appendages | ||||
Pruritus Rash | 36% 24% | 20% 19% | 15% 10% | 7% 4% |
Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”
The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids and azathioprine (AZA) in combination with tacrolimus (n=157) or cyclosporine (n=157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%) and other (1%).
The most common adverse reactions ( ≥ 15%) observed in tacrolimus-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.
Adverse reactions in heart transplant patients in the European trial are presented below:
Tacrolimus/AZA (N=157) | Cyclosporine/AZA (N=157) | |
Cardiovascular System | ||
Hypertension | 62% | 69% |
Pericardial Effusion | 15% | 14% |
Body as a Whole | ||
CMV Infection | 32% | 30% |
Infection | 24% | 21% |
Metabolic and Nutritional Disorders | ||
Diabetes Mellitus | 26% | 16% |
Hyperglycemia | 23% | 17% |
Hyperlipemia | 18% | 27% |
Hemic and Lymphatic System | ||
Anemia | 50% | 36% |
Leukopenia | 48% | 39% |
Urogenital System | ||
Kidney Function Abnormal | 56% | 57% |
Urinary Tract Infection | 16% | 12% |
Respiratory System | ||
Bronchitis | 17% | 18% |
Nervous System | ||
Tremor | 15% | 6% |
In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm.
In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and tacrolimus in combination with sirolimus (n=109), tacrolimus in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75), the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%).
Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with tacrolimus and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%)
Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia,
New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥126 mg/dL, HbA1C≥ 6%, insulin use ≥ 30 days or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10)
Parameter | Treatment Group | |
Tacrolimus/MMF (N = 212) | NEORAL/MMF (N = 212) | |
NODAT | 112/150 (75%) | 93/152 (61%) |
Fasting Plasma Glucose ≥ 126 mg/dL | 96/150 (64%) | 80/152 (53%) |
HbA1C≥ 6% | 59/150 (39%) | 28/152 (18%) |
Insulin Use ≥ 30 days | 9/150 (6%) | 4/152 (3%) |
Oral Hypoglycemic Use | 15/150 (10%) | 5/152 (3%) |
In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criteria of “use of insulin for 30 or more consecutive days with < 5 day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14. PTDM was reported in 20% of Tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 11). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12).
| Status of PTDMUse of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. | Tacrolimus/AZA | CsA/AZA |
Patients without pre-transplant history of diabetes mellitus | 151 | 151 |
New onset PTDM , 1stYear | 30/151 (20%) | 6/151 (4%) |
Still insulin-dependent at one year in those without prior history of diabetes | 25/151 (17%) | 5/151 (3%) |
New onset PTDM post 1 year | 1 | 0 |
Patients with PTDM at 2 years | 16/151 (11%) | 5/151 (3%) |
Patient Race | Patients Who Developed PTDM Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. | |
Tacrolimus | Cyclosporine | |
| African-American | 15/41 (37%) | 3 (8%) |
Hispanic | 5/17 (29%) | 1 (6%) |
Caucasian | 10/82 (12%) | 1 (1%) |
Other | 0/11 (0%) | 1 (10%) |
Total | 30/151 (20%) | 6 (4%) |
Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively, (Table 13). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment
Status of PTDM Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. | US Trial | European Trial | ||
Tacrolimus | Cyclosporine | Tacrolimus | Cyclosporine | |
Patients at riskPatients without pre-transplant history of diabetes mellitus. | 239 | 236 | 239 | 249 |
New Onset PTDM | 42 (18%) | 30 (13%) | 26 (11%) | 12 (5%) |
Patients still on insulin at 1 year | 23 (10%) | 19 (8%) | 18 (8%) | 6 (2%) |
Insulin-dependent PTDM was reported in 13% and 22% of tacrolimus-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 14). Hyperglycemia defined as two fasting plasma glucose levels ≥126 mg/dL was reported with the use of tacrolimus plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment
Status of PTDM Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. | US Trial | European Trial | ||
Tacrolimus/MMF | Cyclosporine/MMF | Tacrolimus/AZA | Cyclosporine/AZA | |
Patients at riskPatients without pre-transplant history of diabetes mellitus. | 75 | 83 | 132 | 138 |
New Onset PTDM | 10 (13%) | 6 (7%) | 29 (22%) | 5 (4%) |
Patients still on insulin at 1 year7 to 12 months for the U.S. trial. | 7 (9%) | 1 (1%) | 24 (18%) | 4 (3%) |
The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.
• Nervous System
• Special Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitus
• Gastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis
• Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation
• Urogenital: Acute kidney failure
• Hemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased
• Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, feeling abnormal, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer
• Musculoskeletal: Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis
• Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration
• Skin : Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating
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.
The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug.
Other reactions include:
• Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease
• Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia [
• Infections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; polyoma virus-associated nephropathy (PVAN) including graft loss [
• Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased
• Miscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction
• Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)
• Nervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES) [
• Respiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure
• Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis
• Special Senses: Blindness, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia
• Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome