Tacrolimus

Check Drug InteractionsCheck known drug interactions.

Tacrolimus Prescribing Information

Increased risk for developing serious infections and malignancies with Tacrolimus Capsules USP or other immunosuppressants that may lead to hospitalization or death.

(

5.1 Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including Tacrolimus Capsules USP are at increased risk of developing lymphomas and other malignancies, particularly of the skin

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 broad-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 Infections

Patients receiving immunosuppressants, including Tacrolimus Capsules USP 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 ]

)

Tacrolimus Capsules USP is a calcineurin-inhibitor immuno-suppressant indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart or lung transplants, in combination with other immunosuppressants. (

1.1 Prophylaxis of Organ Rejection in Kidney, Liver, Heart or Lung Transplant

Tacrolimus Capsules USP is indicated for the prophylaxis of organ rejection, in adult and pediatric patients receiving allogeneic kidney transplant

[see Clinical Studies ],

liver transplants

[see Clinical Studies ],

heart transplant

[see Clinical Studies ],

or lung transplant

[see Clinical Studies ]

in combination with other immunosuppressants.

)

Administer capsules consistently with or without food. (
2.1 Important Administration Instructions
Tacrolimus Capsules USP should not be used without supervision by a physician with experience in immunosuppressive therapy.

Tacrolimus Capsules USP and Tacrolimus Granules 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 capsules are 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 ]

Oral Formulations (Capsules)

If patients are able to initiate oral therapy, the recommended starting doses should be initiated. Tacrolimus Capsules USP may be taken with or without food. However, since the presence of food affects the bioavailability of Tacrolimus Capsules USP, 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 USP
[see Drug Interactions ]

Tacrolimus Capsules USP should not be used simultaneously with cyclosporine. Tacrolimus Capsules USP or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated Tacrolimus Capsules USP 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 USP
[see Dosage and Administration ]

)
Therapeutic drug monitoring is recommended. (
2.1 Important Administration Instructions
Tacrolimus Capsules USP should not be used without supervision by a physician with experience in immunosuppressive therapy.

Tacrolimus Capsules USP and Tacrolimus Granules 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 capsules are 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 ]

Oral Formulations (Capsules)

If patients are able to initiate oral therapy, the recommended starting doses should be initiated. Tacrolimus Capsules USP may be taken with or without food. However, since the presence of food affects the bioavailability of Tacrolimus Capsules USP, 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 USP
[see Drug Interactions ]

Tacrolimus Capsules USP should not be used simultaneously with cyclosporine. Tacrolimus Capsules USP or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated Tacrolimus Capsules USP 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 USP
[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 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.
)
Avoid eating grapefruit or drinking grapefruit juice. (
2.1 Important Administration Instructions
Tacrolimus Capsules USP should not be used without supervision by a physician with experience in immunosuppressive therapy.

Tacrolimus Capsules USP and Tacrolimus Granules 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 capsules are 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 ]

Oral Formulations (Capsules)

If patients are able to initiate oral therapy, the recommended starting doses should be initiated. Tacrolimus Capsules USP may be taken with or without food. However, since the presence of food affects the bioavailability of Tacrolimus Capsules USP, 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 USP
[see Drug Interactions ]

Tacrolimus Capsules USP should not be used simultaneously with cyclosporine. Tacrolimus Capsules USP or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated Tacrolimus Capsules USP 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 USP
[see Dosage and Administration ]

)

See dosage adjustments for African-American patients (

2.2 Dosage recommendation for Adult Kidney, Liver, Heart or LungTransplant Patients - Capsules

Capsules

If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated. The initial dose of Tacrolimus Capsules USP should be administered no sooner than 6 hours after transplantation in the liver, heart or lung transplant patients. In kidney transplant patients, the initial dose of Tacrolimus Capsules USP may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered.

The initial oral Tacrolimus Capsules USP dosage recommendations for adult patients with kidney, liver, heart or lung 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 USP Dosage Recommendations and Whole Blood Trough Concentration Range in Adults
¹African-American patients may require higher doses compared to Caucasians (see Table 2)
²In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL during month 1-3 and 5-12 ng/mL during month 4-12 [see Clinical Studies ]
³Patients with cystic fibrosis may require higher doses due to lower bioavailability [see Clinical Pharmacology ]
Patient Population	Tacrolimus Capsules USP¹Initial Oral Dosage	Whole Blood Trough Concentration Range
Kidney Transplant
With Azathioprine	0.2 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL
With MMF/IL-2 receptor antagonist²	0.1 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-12: 4-11 ng/mL
Liver Transplant
With corticosteroids only	0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-12: 5-20 ng/mL
Heart Transplant
With azathioprine or MMF	0.075 mg/kg/day, divided in two doses, administered every 12 hours	Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL
Lung Transplant
With azathioprine or MMF	0.075 mg/kg/day³, divided in two doses, administered every 12 hours	Month 1-3: 10-15 ng/mL Month 4-12: 8-12 ng/mL

Dosage should be titrated based on clinical assessments of rejection and tolerability. Tacrolimus Capsules USP 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	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

In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor Tacrolimus trough concentrations and adjust the dose accordingly.

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 USP 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, and 0.01-0.03 mg/kg/day in lung 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 pertain to oral administration of Tacrolimus Capsules USP 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 USP at the lower end of the therapeutic dosing range in patients who have received a liver, heart or lung 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 USP 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. Close monitoring of blood concentrations is warranted.

The use of Tacrolimus Capsules USP 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

ADULT
Patient Population	Initial Oral Dosage (formulation)	Whole Blood Trough Concentration Range
Kidney Transplant
With azathioprine	0.2 mg/kg/day capsules, divided in two doses, every 12 hours	Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL
With MMF/IL-2 receptor antagonist	0.1 mg/kg/day capsules, divided in two doses, every 12 hours	Month 1-12: 4-11 ng/mL
Liver Transplant
With corticosteroids only	0.1-0.15 mg/kg/day capsules, divided in two doses, every 12 hours	Month 1-12: 5-20 ng/mL
Heart Transplant
With azathioprine or MMF	0.075 mg/kg/day capsules, divided in two doses, every 12 hours	Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL
Lung Transplant
With azathioprine or MMF	0.075 mg/kg/day¹ capsules, divided in two doses, every 12 hours	Month 1-3: 10-20 ng/mL Month 4-12: 8-12 ng/mL

MMF= Mycophenolate mofetil
^{1. Patients with cystic fibrosis may require higher doses due to lower bioavailability.}
^{2. Dose at 0.1 mg/kg/day if antibody induction treatment is administered}^.
PEDIATRIC
Patient Population	Initial Oral Dosage (formulation)	Whole Blood Trough Concentration Range
Kidney Transplant
	0.3 mg/kg/day capsules divided in two doses, every 12 hours	Month 1-12: 5-20 ng/mL
Liver Transplant
	0.15-0.2 mg/kg/day capsules divided in two doses, every 12 hours	Month 1-12: 5-20 ng/mL
Heart Transplant
	0.3 mg/kg/day² capsules divided in two doses, every 12 hours	Month 1-12: 5-20 ng/mL
Lung Transplant
	0.3 mg/kg/day^{1, 2}capsules divided in two doses, every 12 hours	Weeks 1-2: 10-20 ng/mL Week 2 to Month 12: 10-15 ng/mL

Tacrolimus Capsules USP are available in the following dosage form and strengths:

Oblong shape, hard gelatin capsules for oral administration contains Tacrolimus as follows:

Tacrolimus Capsules USP, 0.5 mg: Light yellow color, oblong shape, size "5" hard gelatin capsules printed with "PBT" and "0.5" in red ink on body and cap respectively.
Tacrolimus Capsules USP, 1 mg: White color, oblong shape, size "5" hard gelatin capsules printed with "PBT" and "1.0" in red ink on body and cap respectively.
Tacrolimus Capsules USP, 5 mg: Pink color, oblong shape, size "4" hard gelatin capsules printed with "PBT" and "5.0" in red ink on body and cap respectively.

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 Capsules USP 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/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

^{1 Includes multiple births and terminations.}
^{2 Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.}
	Kidney	Liver
Pregnancy Outcomes¹	462	253
Miscarriage	24.50%	25%
Live births	331	180
Pre-term delivery (< 37 weeks)	49%	42%
Low birth weight (< 2500 g)	42%	30%
Birth defects	8%²	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 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 1.0 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 ]

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 , Nonclinical Toxicology ]

Infertility

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

[see Nonclinical Toxicology ]

)

Tacrolimus Capsules USP are contraindicated in patients with a hypersensitivity to tacrolimus. Tacrolimus injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome

[see Adverse Reactions (

6 ADVERSE REACTIONS

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

Lymphoma and Other Malignancies
[see Warnings and Precautions ]
Serious Infections
[see Warnings and Precautions ]
New Onset Diabetes After Transplant
[see Warnings and Precautions ]
Nephrotoxicity
[see Warnings and Precautions ]
Neurotoxicity
[see Warnings and Precautions ]
Hyperkalemia
[see Warnings and Precautions ]
Hypertension
[see Warnings and Precautions ]
Anaphylactic Reactions with Tacrolimus Injection
[see Warnings and Precautions ]
Myocardial Hypertrophy
[see Warnings and Precautions ]
Pure Red Cell Aplasia
[see Warnings and Precautions ]
Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [
see Warnings and Precautions
(
5.16
)]

The most common adverse reactions (≥15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia.

To report SUSPECTED ADVERSE REACTIONS, contact Panacea Biotec Pharma Ltd. at 1-877-687-4130 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

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.

Kidney Transplantation

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 a 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 reactions 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:

Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)
	Tacrolimus/AZA (N=205)	Cyclosporine/AZA (N=207)
Nervous System
Tremor	54%	34%
Headache	44%	38%
Insomnia	32%	30%
Paresthesia	23%	16%
Dizziness	19%	16%
Gastrointestinal
Diarrhea	44%	41%
Nausea	38%	36%
Constipation	35%	43%
Vomiting	29%	23%
Dyspepsia	28%	20%
Cardiovascular
Hypertension	50%	52%
Chest Pain	19%	13%
Urogenital
Creatinine Increased	45%	42%
Urinary Tract Infection	34%	35%
Metabolic and Nutritional
Hypophosphatemia	49%	53%
Hypomagnesemia	34%	17%
Hyperlipemia	31%	38%
Hyperkalemia	31%	32%
Diabetes Mellitus	24%	9%
Hypokalemia	22%	25%
Hyperglycemia	22%	16%
Edema	18%	19%
Hemic and Lymphatic
Anemia	30%	24%
Leukopenia	15%	17%
Miscellaneous
Infection	45%	49%
Peripheral Edema	36%	48%
Asthenia	34%	30%
Abdominal Pain	33%	31%
Pain	32%	30%
Fever	29%	29%
Back Pain	24%	20%
Respiratory System
Dyspnea	22%	18%
Cough Increased	18%	15%
Musculoskeletal
Arthralgia	25%	24%
Skin
Rash	17%	12%
Pruritus	15%	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:

Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)
	Tacrolimus Capsules USP (Group C) (N=403)	Cyclosporine (Group A) (N=384)	Cyclosporine (Group B) (N=408)
Diarrhea	25%	16%	13%
Urinary tract infection	24%	28%	24%
Anemia	17%	19%	17%
Hypertension	13%	14%	12%
Leucopenia	13%	10%	10%
Edema peripheral	11%	12%	13%
Hyperlipidemia	10%	15%	13%
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

In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n = 212) or cyclosporine (n = 212) in combination with MMF1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77), the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below:

Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)
	Tacrolimus Capsules USP / MMF (N=212)	Cyclosporine / MMF (N=212)
Gastrointestinal Disorder
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 Disorder
Hypomagnesemia	28%	22%
Hypophosphatemia	28%	21%
Hyperkalemia	26%	19%
Hyperglycemia	21%	15%
Hyperlipidemia	18%	25%
Hypokalemia	16%	18%
Nervous System Disorder
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 "Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies".

Liver Transplantation

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 to 70), 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 (≥ 40%) 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 and IV 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 reactions 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.

Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus
	U.S.TRIAL		EUROPEAN TRIAL
	Tacrolimus (N=250)	Cyclosporine/AZA (N=250)	Tacrolimus (N=264)	Cyclosporine /AZA (N=265)
Nervous System
Headache	64%	60%	37%	26%
Insomnia	64%	68%	32%	23%
Tremor	56%	46%	48%	32%
Paresthesia	40%	30%	17%	17%
Gastrointestinal
Diarrhea	72%	47%	37%	27%
Nausea	46%	37%	32%	27%
LFT Abnormal	36%	30%	6%	5%
Anorexia	34%	24%	7%	5%
Vomiting	27%	15%	14%	11%
Constipation	24%	27%	23%	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	48%	45%	16%	9%
Hyperglycemia	47%	38%	33%	22%
Hyperkalemia	45%	26%	13%	9%
Hypokalemia	29%	34%	13%	16%
Hemic and Lymphatic
Anemia	47%	38%	5%	1%
Leukocytosis	32%	26%	8%	8%
Thrombocytopenia	24%	20%	14%	19%
Miscellaneous
Pain	63%	57%	24%	22%
Abdominal Pain	59%	54%	29%	22%
Asthenia	52%	48%	11%	7%
Fever	48%	56%	19%	22%
Back Pain	30%	29%	17%	17%
Ascites	27%	22%	7%	8%
Peripheral Edema	26%	26%	12%	14%
Respiratory System
Pleural Effusion	30%	32%	36%	35%
Dyspnea	29%	23%	5%	4%
Atelectasis	28%	30%	5%	4%
Skin and Appendages
Pruritus	36%	20%	15%	7%
Rash	24%	19%	10%	4%

Table 8. Pediatric Liver Transplantation: Adverse Reactions Occurring in > 10% of Patients Treated with Tacrolimus Granules (STUDY 01-13)
	Tacrolimus Granules (N=91)	Cyclosporine (N=90)
Body as a Whole
Fever	46%	51%
Infection	25%	29%
Sepsis	22%	20%
CMV Infection	15%	24%
EBV Infection	26%	11%
Ascites	17%	20%
Peritonitis	12%	7%
Cardiovascular System
Hypertension	39%	47%
Digestive System
Liver Function Tests Abnormal	37%	28%
Diarrhea	26%	26%
Vomiting	15%	13%
Gastrointestinal Hemorrhage	11%	12%
Bile Duct Disorder	12%	8%
Gastroenteritis	12%	4%
Hemic and Lymphatic System
Anemia	29%	19%
Metabolic and Nutritional Disorders
Hypomagnesemia	40%	29%
Acidosis	26%	17%
Hyperkalemia	12%	10%
Respiratory System
Pleural Effusion	22%	19%
Bronchitis	11%	8%
Urogenital System
Kidney Function Abnormal	13%	14%

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"

Heart Transplantation

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 reactions 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:

Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus Capsules USP in Conjunction with Azathioprine (AZA)
	Tacrolimus Capsules USP /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%), hypertriglyceridemia (65%), anemia (hemoglobin < 10.0 g/dL) (65%), fasting blood glucose > 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs < 3000 cells/mcL (34%), serious bacterial infections (30%), magnesium < 1.2 mEq/L (24%), platelet count < 75,000 cells/mcL (19%), and other opportunistic infections (15%).

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,

Candida

infection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection "Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies."

New Onset Diabetes After Transplant

Kidney Transplantation

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)

[see Clinical Studies

Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)
Parameter	Treatment Group
Parameter	Tacrolimus Capsules USP/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 criterion 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)

Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)
^{1 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.}
Status of PTDM1	Tacrolimus Capsules USP/AZA				CsA/AZA
Patients without pre-transplant history of diabetes mellitus.		151		151
New onset PTDM¹, 1^stYear	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 PTDM¹post 1 year	1		0
Patients with PTDM¹at 2 years	16/151 (11%)		5/151 (3%)

Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial
Patient Race	Patients Who Developed PTDM ¹
Patient Race	Tacrolimus Capsules USP	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%)

Liver Transplantation

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

[see Adverse Reactions ]

Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients
^{1Use 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.}
^{2 Patients without pre-transplant history of diabetes mellitus}
Status of PTDM¹	US Trial		European Trial
Status of PTDM¹	Tacrolimus Capsules USP	Cyclosporine	Tacrolimus Capsules USP	Cyclosporine
Patients at risk²	239	236	239	249
New Onset PTDM¹	42 (18%)	30 (13%)	26 (11%)	12 (5%)
Patients still on insulin at 1 year	23 (10%)	19 (8%)	18 (8%)	6 (2%)

Heart Transplantation

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

[see Adverse Reactions ]

Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients
¹Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
²Patients without pre-transplant history of diabetes mellitus.
³7-12 months for the U.S. trial.
Status of PTDM¹	US Trial		European Trial
Status of PTDM¹	Tacrolimus Capsules USP/MMF	Cyclosporine/MMF	Tacrolimus Capsules USP/AZA	Cyclosporine/AZA
Patients at risk²	75	83	132	138
New Onset PTDM¹	10 (13%)	6 (7%)	29 (22%)	5 (4%)
Patients still on insulin at 1 year³	7 (9%)	1 (1%)	24 (18%)	4 (3%)

Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies

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
:
Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired
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, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis
Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation
Urogenital: Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis
Metabolic/Nutritional: Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increase, weight gain
Endocrine: Cushing's syndrome
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, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer
Musculoskeletal: Arthralgia, cramps, generalized spasm, 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 ulcer, sweating

Lung Transplantation

Adverse reactions in lung transplant patients were similar to those in kidney, liver, or heart transplant patients treated with Tacrolimus Capsules USP

[see

Adverse Reactions ( 6.2

)].

6.2 Postmarketing Experience

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:

Cardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation,
Torsade de Pointes
venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy.
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, pancytopenia, thrombotic thrombocytopenic purpura, pure red cell aplasia, thrombotic microangiopathy.
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)
,
progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope
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

Postmarketing Adverse Reactions in Lung Transplantation.

Based on U.S. Scientific Registry of Transplant Recipients (SRTR) data, published clinical trials, and postmarketing reports, the safety profile for lung transplant patients treated with Tacrolimus Capsules USP is consistent with the safety profile in kidney, liver, and heart transplant patients treated with Tacrolimus Capsules USP. The primary adverse reactions described include renal dysfunction, infection, diabetes, gastrointestinal disturbances (e.g., diarrhea), hypertension, and neurological events (e.g., tremor). As expected, lung transplant patients have a higher incidence of pulmonary complications (e.g., pneumonia, bronchiolitis obliterans syndrome) than other solid organ transplant patients, which is in part due to the underlying disease and to the nature of the transplanted organ.

)]

Report Adverse Event

Tacrolimus

Tacrolimus Prescribing Information

Tacrolimus PubMed™ News