Tacrolimus

Warnings and Precautions (

Warnings and Precautions, Cannabidiol Drug Interactions (

Tacrolimus capsules are a 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. (

• •Intravenous (IV) use recommended for patients who cannot tolerate oral formulations (capsules). (
  2.1 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 Clinical Pharmacology ]

  .

  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 ].
  ,
  2.2 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.

  Table 1. Summary of Initial Oral Tacrolimus Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults

  With AzathioprineWith MMF/IL-2 receptor antagonist

  ^†

  With corticosteroids onlyWith azathioprine or MMF

  Patient Population	Tacrolimus Capsules*Initial Oral Dosage	Whole Blood Trough Concentration Range
  Kidney Transplant
  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
  0.1 mg/kg/day, divided in two doses, administered every 12 hours	Month 1 to 12: 4 to 11 ng/mL
  Liver Transplant
  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
  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

  ^*African-American patients may require higher doses compared to Caucasians

  (see Table 2).

  ^†In a second smaller trial, the initial dose of tacrolimus was 0.15 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during month 1 to 3 and 5 to 12 ng/mL during month 4 to 12

  [see Clinical Studies ]

  .

  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 ]

  .

  Table 2. Comparative Dose and Trough Concentrations Based on Race

  Time After Transplant	Caucasian N = 114		African-American N = 56
  	Dose (mg/kg)	Trough Concentrations (ng/mL)	Dose (mg/kg)	Trough Concentrations (ng/mL)
  Day 7	0.18	12	0.23	10.9
  Month 1	0.17	12.8	0.26	12.9
  Month 6	0.14	11.8	0.24	11.5
  Month 12	0.13	10.1	0.19	11

  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 ]

  .
  )
• •Administer capsules consistently with or without food. (
  2.1 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 Clinical Pharmacology ]

  .

  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 ].
  )
• •Therapeutic drug monitoring is recommended. (
  2.1 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 Clinical Pharmacology ]

  .

  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 ].
  ,
  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. 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 the 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) anticoagulant. Heparin anticoagulation 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.

  Additional pediatric use and lung transplant 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.
  )
• •Avoid eating grapefruit or drinking grapefruit juice. (
  2.1 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 Clinical Pharmacology ]

  .

  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 ].
  )
• •See dosage adjustments for African-American patients (
  2.2 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.

  Table 1. Summary of Initial Oral Tacrolimus Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults

  With AzathioprineWith MMF/IL-2 receptor antagonist

  ^†

  With corticosteroids onlyWith azathioprine or MMF

  Patient Population	Tacrolimus Capsules*Initial Oral Dosage	Whole Blood Trough Concentration Range
  Kidney Transplant
  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
  0.1 mg/kg/day, divided in two doses, administered every 12 hours	Month 1 to 12: 4 to 11 ng/mL
  Liver Transplant
  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
  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

  ^*African-American patients may require higher doses compared to Caucasians

  (see Table 2).

  ^†In a second smaller trial, the initial dose of tacrolimus was 0.15 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during month 1 to 3 and 5 to 12 ng/mL during month 4 to 12

  [see Clinical Studies ]

  .

  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 ]

  .

  Table 2. Comparative Dose and Trough Concentrations Based on Race

  Time After Transplant	Caucasian N = 114		African-American N = 56
  	Dose (mg/kg)	Trough Concentrations (ng/mL)	Dose (mg/kg)	Trough Concentrations (ng/mL)
  Day 7	0.18	12	0.23	10.9
  Month 1	0.17	12.8	0.26	12.9
  Month 6	0.14	11.8	0.24	11.5
  Month 12	0.13	10.1	0.19	11

  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 ]

  .
  ), hepatic and renal impaired. (
  2.4 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 ]

  .
  ,
  2.5 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 ]

  .
  ) For complete dosing information, see the Full Prescribing Information

MMF= Mycophenolate mofetil

Tacrolimus Capsules, USP are hard gelatin capsules for oral administration containing anhydrous tacrolimus, USP as follows:

• •0.5 mg: Size “4” hard gelatin capsule with light yellow cap and light yellow body, imprinted with a Glenmark logo “G” on the cap and “685” on the body in red ink, filled with white to off-white granular powder.
• •1 mg: Size “4” hard gelatin capsule with white cap and white body, imprinted with a Glenmark logo “G” on the cap and “686” on the body in red ink, filled with white to off-white granular powder.
• •5 mg: Size “4” hard gelatin capsule with greyish red cap and greyish red body, imprinted with a Glenmark logo “G” on the cap and “687” on the body in white ink, filled with white to off-white granular powder.

•  Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. (
  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 mg/kg/day 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 Considerations

  Disease-Associated Maternal and/or Embryo-Fetal Risk

  Risks 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 Reactions

  Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly

  [see Warnings and Precautions ]

  .

  Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure

  [see Warnings and Precautions ]

  .

  Fetal/Neonatal Adverse Reactions

  Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking tacrolimus.

  Labor or Delivery

  There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus.

  Data

  Human Data

  There 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 Tacrolimus

  Miscarriage

  Live births

  Pre-term delivery (< 37 weeks)Low birth weight (< 2500 g)Birth defects

  	Kidney	Liver
  Pregnancy Outcomes*	462	253
  24.5%	25%
  331	180
  49%	42%
  42%	30%
  8%†	5%

  ^*Includes multiple births and terminations.

  †Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.

  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 Data

  Administration 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 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 ]

  .
  ,
  8.3 Females and Males of Reproductive Potential

  Contraception

  Tacrolimus 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 and Nonclinical Toxicology ]

  .

  Infertility

  Based on findings in animals, male and female fertility may be compromised by treatment with tacrolimus

  [see Nonclinical Toxicology ]

  .
  )