1.1 Prophylaxis of Organ Rejection in Kidney, Liver, and Heart Transplant

Tacrolimus Capsules is indicated for the prophylaxis of organ rejection, in patients receiving allogeneic kidney transplant  [see Clinical Studies ( 14.1)] , liver transplants  [see Clinical Studies ( 14.2)]  and heart transplant  [see Clinical Studies ( 14.3)] , in combination with other immunosuppressants.

2.1 Important Administration Instructions

Tacrolimus Capsules should not be used without supervision by a physician with experience in immunosuppressive therapy.

Tacrolimus capsules 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 ( 5.3)].
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 ( 5.9)].

Oral Formulations (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 ( 12.3)].

General Administration Instructions

Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules  [see Drug Interactions ( 7.2)].

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 Dosage and Administration ( 2.6)].

2.2 Dosing for Adult Kidney, Liver, or Heart Transplant 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 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 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.

*African-American patients may require higher doses compared to Caucasians  (see Table 2)

† In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 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 ( 14.1)].

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)  [see Use in Specific Populations ( 8.8) and Clinical Pharmacology ( 12.3)].

Table 2. Comparative Dose and Trough Concentrations Based on Race

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 8-12 hours after discontinuing the intravenous infusion.

The recommended starting dose of tacrolimus injection is 0.03-0.05 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 pertain to oral administration of tacrolimus capsules 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 ( 5.9)].

2.3 Dosing for Pediatric Kidney, Liver, and Heart Transplant Patients

Oral formulation (capsules)

Pediatric patients in general need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosing for pediatric transplant patients and whole blood trough concentration range are shown in  Table 3. Perform TDM to ensure that patients are  within the ranges listed in Table 3.

Table 3. Summary of Initial Tacrolimus capsules Dosing Recommendations and Whole Blood Trough Concentration Range in Children

*0.1 mg/kg/day if cell depleting induction treatment is administered

† See  Clinical Pharmacology ( 12.3) , Tacrolimus Granules Pharmacokinetics in Pediatric Patients
‡ See Clinical Studies ( 14.2) , Liver Transplantation

For conversion of pediatric patients from tacrolimus granules to tacrolimus capsules or from tacrolimus capsules to tacrolimus granules, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration ( 2.6)] . If a patient is unable to receive an oral formulation, the patient may be started on tacrolimus injection. For pediatric liver transplant patients, the intravenous dose is 0.03-0.05 mg/kg/day.

2.4 Dosage Adjustment in Patients with Renal Impairment

Due to its potential for nephrotoxicity, consideration should be given to 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 ( 2.2) , Warnings and Precautions ( 5.5) , Use in Specific Populations ( 8.6) , and Clinical Pharmacology ( 12.3)] .

2.5 Dosage Adjustments in 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 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 ( 2.2), Warnings and Precautions ( 5.5), Use in Specific Populations ( 8.7), and Clinical Pharmacology ( 12.3)].

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) 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.

5.1 Lymphoma and Other Malignancies

Patients 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 changese; xposure 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 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:

• Polyoma virus-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)].

5.3 Not Interchangeable With Extended-Release Tacrolimus Products - Medication Errors

Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under-or over-exposure to tacrolimus. Tacrolimus is not interchangeable or substitutable with tacrolimus extended-release products. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision.  Instruct patients and caregivers to recognize the appearance of tacrolimus capsules dosage forms  [see Dosage Forms and Strengths ( 3)] and to confirm with the healthcare provider if a different product is dispensed.

5.4 New Onset Diabetes After Transplant

Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, and heart transplantation. New onset diabetes after  transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations  should be monitored closely in patients using tacrolimus  [see Adverse Reactions ( 6.1)] .

5.5 Nephrotoxicity

Tacrolimus like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity. Nephrotoxicity was reported in clinical trials  [see Adverse Reactions ( 6.1)]. Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range. The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors)  [see Drug Interactions ( 7.2)] . Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

5.6 Neurotoxicity

Tacrolimus may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions ( 6.1, 6.2)] . As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of tacrolimus capsules if neurotoxicity occurs.

5.7 Hyperkalemia

Hyperkalemia has been reported with tacrolimus use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of  other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during tacrolimus therapy  [see Adverse Reactions ( 6.1)] . Monitor serum potassium levels periodically during treatment

5.8 Hypertension

Hypertension is a common adverse effect of tacrolimus therapy and may require antihypertensive therapy  [see Adverse Reactions ( 6.1)].  The control of blood pressure can be accomplished with any of the common antihypertensive  agents, though careful consideration should be given prior to use of antihypertensive agents associated with  hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers)  [see Warnings and Precautions ( 5.7)]. Calcium-channel blocking agents  may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus  [see Drug Interactions ( 7.2)].

5.9 Anaphylactic Reactions with Tacrolimus Injection

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take tacrolimus capsules orally. Monitor patients for anaphylaxis when using the intravenous route of administration [ see Dosage and Administration ( 2.1)].

5.10 Not Recommended for Use with Sirolimus

Tacrolimus capsules are not recommended for use with sirolimus:

• The use of sirolimus with tacrolimus in studies of  de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT) and is not recommended.
• The use of sirolimus (2 mg per day) with tacrolimus in heart transplant patients in a U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies ( 14.3)].

5.11 Interactions with CYP3A4 Inhibitors and Inducers

When co-administering tacrolimus with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended  [see Drug Interactions ( 7)].

5.12 QT Prolongation

Tacrolimus may prolong the QT/QTc interval and may cause  Torsade de Pointes. Avoid tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

When co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.

Use of tacrolimus with amiodarone has been reported to result in increased tacrolimus whole blood  concentrations with or without  concurrent QT prolongation  [see Drug Interactions ( 7)].

5.13 Myocardial Hypertrophy

Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by  echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most  cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations  of ventricular dysfunction while receiving  tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus capsules should be  considered  [see Adverse Reactions ( 6.2)].

5.14 Immunizations

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with Tacrolimus.

The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with tacrolimus.

5.15 Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All  patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed,  discontinuation of tacrolimus capsules should be considered  [see Adverse Reactions ( 6.2)].

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.

6.2 Postmarketing Adverse Reactions

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:

7.1 Mycophenolic Acid

When tacrolimus is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with tacrolimus co-administration than with  cyclosporine co-administration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA associated adverse  reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.

7.2 Effects of Other Drugs on Tacrolimus

Table 15 displays the effects of other drugs on tacrolimus.

* Tacrolimus dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology ( 12.3)] , literature reports of altered tacrolimus exposures, or the other drug's known CYP3A inhibitor/inducer status.

† High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor.

# Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate).

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to tacrolimus during pregnancy. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus. Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org/.

Risk Summary

Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress  [see Human Data]. Advise pregnant women of the potential risk to the fetus. Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was  associated with maternal toxicity/lethality, and an  increased incidence of abortion, malformation and embryofetal death at clinically relevant doses (0.5 to 6.9 times the recommended clinical dose range [0.2 to 0.075  mg/kg/day], on a mg/m 2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses  (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations  and skeletal effects were observed in offspring that died  [see Animal Data].

The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Risks during pregnancy are increased in organ transplant recipients.

The risk of premature delivery following 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 ( 5.4)].

Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure  [see Warnings and Precautions ( 5.7, 5.8)].

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

* 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/m 2 basis). 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)].

8.2 Lactation

Risk Summary

Controlled lactation studies have not been conducted in humans; however tacrolimus has been reported to be present in human milk. The effects of tacrolimus  on the breastfed infant, or on milk production have not been assessed.  Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies, exposure to tacrolimus during  the  postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses  [see Pregnancy ( 8.1), Nonclinical Toxicology ( 13.1)].

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tacrolimus and any  potential adverse effects on the  breastfed child from tacrolimus or from the underlying maternal condition.

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 ( 8.1), Nonclinical Toxicology ( 13.1)].

Infertility

Based on findings in animals, male and female fertility may be compromised by treatment with tacrolimus  [see Nonclinical Toxicology ( 13.1)].

8.4 Pediatric Use

Safety and effectiveness have been established in pediatric liver, kidney, and heart transplant patients.

Liver transplant:

Safety and efficacy using tacrolimus Granules in pediatric  de novo liver transplant patients less than 16 years of age are based on evidence from active controlled  studies  that included 56 pediatric patients, 31 of which received tacrolimus and supported by two pharmacokinetic and safety studies in 151 children who received tacrolimus.

Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the  PK  studies based on clinical status and whole blood concentrations. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations  of tacrolimus similar to adult patients  [see Dosage and Administration ( 2.3), Adverse Reactions ( 6.1), Clinical Pharmacology ( 12.3)  and Clinical Studies ( 14.2)].

Kidney and heart transplant:

Use of Tacrolimus capsules and tacrolimus Granules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients  [see Dosage and Administration ( 2.3) and Clinical Pharmacology ( 12.3)].

8.5 Geriatric Use

Clinical trials of tacrolimus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other  reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or  cardiac function, and of concomitant disease or other drug therapy.

8.6 Use in Renal Impairment

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, 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  [see Dosage and Administration ( 2.4) and Clinical Pharmacology ( 12.3)].

8.7 Hepatic Impairment

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy volunteers  with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment  [see Clinical Pharmacology ( 12.3)].

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 trough 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 ( 2.5) and Clinical Pharmacology  ( 12.3)].

8.8 Race or Ethnicity

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)].

African-American and Hispanic patients are at increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately [see Warnings and Precautions ( 5.4)].

12.1 Mechanism of Action

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular  enzyme) is then formed, after which the phosphatase activity of calcineurin inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors  such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB).

Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon,  tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces  apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

12.3 Pharmacokinetics

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean ± S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients ( Table 17).

Table 17. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients

* not applicable

† AUC0-inf

‡ not available

§ AUC0-t

¶ Determined after the first dose

# Median [range]
Þ AUC0-12

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy  [see Dosage and Administration ( 2.6)] . Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe  tacrolimus pharmacokinetics.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used  in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day)  [see Boxed Warning and Warnings and Precautions ( 5.1)] .

A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m 2/day. In the study, the incidence of skin tumors was minimal  and the topical application of tacrolimus was not associated with skin tumor formation under  ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the  mouse dermal carcinogenicity study at  a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity  study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus  use is  unknown.

The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis.

Mutagenesis

No evidence of genotoxicity was seen in bacterial ( Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells)  in vitro assays of mutagenicity, the  in vitro CHO/HGPRT assay of mutagenicity, or  in vivo clastogenicity  assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Impairment of Fertility

Tacrolimus subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m 2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range) resulted in a dose-related decrease in sperm count. Tacrolimus administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as  to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal  effects were indicated by a higher rate of pre-and post- implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal  and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

14.1 Kidney Transplantation

14.2 Liver Transplantation

The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded  multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal  corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation.

In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same  CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients  with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤12 years old) were  allowed.

In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases.

One-year patient survival and graft survival in the tacrolimus-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials.The overall 1-year patient survival (CsA/AZA and tacrolimus-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and tacrolimus-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral tacrolimus capsules dosing was 2 days.

Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients often are maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation ranged from 9.8 ng/mL to 19.4 ng/mL.

Pediatric Liver Transplantation Using Tacrolimus Granules

The efficacy and safety of Tacrolimus Granules plus corticosteroids were compared with a triple regimen of cyclosporine/corticosteroids/azathioprine in a randomized, open-label study, in  de novo pediatric liver transplant patients. The  study was conducted outside the United States and enrolled patients aged 16 years or younger.  The distribution of pediatric patients by age was similar in both treatment groups, with a majority < 5 years. Patients were randomized to either tacrolimus for oral  suspension 0.3 mg/kg/day (N = 91) or cyclosporine 10 mg/kg/day orally (N = 90) initiated 6 hours after completion of transplant surgery. Doses throughout the 1-year  study period were adjusted to maintain whole blood trough levels within 5-20 ng/mL [see Dosage and Administration ( 2.3)] . Based on trough levels, doses of tacrolimus were adjusted to 0.17 mg/kg/day and 0.14 mg/kg/day by days 2 and 3, respectively. At 12 months, the incidence rate of BPAR, graft loss, death, or lost to follow-up was 52.7% in the tacrolimus group and 61.1% in the cyclosporine group ( Table 27).

Table 27. Key Efficacy Results at 12 Months in Pediatric Liver Transplant Recipients Receiving Tacrolimus Granules or Cyclosporine

* 95% confidence interval calculated using normal approximation.

14.3 Heart Transplantation

Two open-label, randomized, comparative trials evaluated the safety and efficacy of tacrolimus-based and cyclosporine­ based immunosuppression in primary orthotopic  heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with tacrolimus or cyclosporine modified for 18 months. In a 3-arm trial conducted in the US, 331 patients received corticosteroids and tacrolimus plus sirolimus, tacrolimus plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year.

In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine  group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the tacrolimus plus MMF group and 86% survival in the cyclosporine  modified plus MMF group. 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. Data from this European trial indicate that from 1 week to 3 months post-transplant, approximately 80% of patients maintained trough concentrations between 8 to 20 ng/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to 18 ng/mL.

The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose tacrolimus; however, this regimen was associated with increased  risk of wound-healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions ( 5.10)].

16.1 Tacrolimus Capsules, USP

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 cap and body respectively.

Capsules are supplied as follows:

NDC 43817- 421-01               Bottle of 100

Tacrolimus Capsules, USP, 1 mg: White color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “1.0” in red ink on cap and body respectively.

Capsules are supplied as follows:

NDC 43817- 422-01            Bottle of 100

Tacrolimus Capsules, USP, 5 mg: Pink color, oblong shape, size “4” hard gelatin capsules printed with “PBT” and “5.0” in red ink on cap and body respectively.

Capsules are supplied as follows:

NDC 43817- 423-01             Bottle of 100

Note: Tacrolimus capsule are not filled to maximum capsule capacity. Capsule contains labeled amount.

Store and Dispense

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

16.4 Handling and Disposal

Tacrolimus can cause fetal harm. Tacrolimus capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in tacrolimus capsules. If such contact  occurs wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures 1.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

17.1 Administration

Advise the patient or caregiver to:

• Inspect their tacrolimus capsules medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact  their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for tacrolimus capsules.
• Take tacrolimus capsules at the same 12-hour intervals every day to achieve consistent blood concentrations.
• Take tacrolimus Ccapsules consistently either with or without food because the presence and composition of food decreases the bioavailability of Tacrolimus Capsules.
• Not to eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules  [see Drug Interactions ( 7.2)].

17.2 Development of Lymphoma and Other Malignancies

Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum  with a high protection factor  [see Boxed Warnings and Warnings and Precautions ( 5.1)].

17.3 Increased Risk of Infection

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Boxed Warnings and Warnings and Precautions ( 5.2)]

17.4 New Onset Diabetes After Transplant

Inform patients that tacrolimus capsules can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst, or hunger  [see Warnings and Precautions ( 5.4)].

17.5 Nephrotoxicity

Inform patients that Tacrolimus capsules can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions ( 5.5)].

17.6 Neurotoxicity

Inform  patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, deliriums, or tremors  [see Warnings and Precautions ( 5.6)].

17.7 Hyperkalemia

Inform patients that tacrolimus capsules can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions ( 5.7)]. 

17.8 Hypertension

Inform patients that tacrolimus capsules can cause high blood pressure which may require treatment with anti-hypertensive therapy. Advise patients to monitor their blood pressure  [see Warnings and Precautions ( 5.8)].

17.9 Drug Interactions

Instruct patients to tell their healthcare providers when they start or stop taking all the medicines, including prescription medicines and non-prescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice  [see Drug Interactions ( 7)].

17.10 Pregnancy, Lactation and Infertility

Inform women of childbearing potential that tacrolimus capsules can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant  [see Use in Specific Populations ( 8.1,  8.2, 8.3)].

Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/[see Use in Specific Populations ( 8.1)].

Based on animal studies, tacrolimus capsules may affect fertility in males and females  [see Nonclinical Toxicology ( 13.1)].

17.11 Myocardial Hypertrophy

Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure).

17.12 Immunizations

Inform patients that tacrolimus capsules can interfere with the usual response to immunizations and that they should avoid live vaccines  [see Warnings and Precautions ( 5.14)].